5-Cyano-2-aminopyrimidine derivatives

ABSTRACT

Pyrimidines of formula (1) are described  
                 
 
     wherein Ar is an optionally substituted aromatic or heteroaromatic group;  
     R 1  is a hydrogen atom or a straight or branched chain alkyl group;  
     R 2  is a —X 1 —R 3  group where X 1  is a direct bond or a linker atom or group, and  
     R 3  is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;  
     and the salts, solvates, hydrates and N-oxides thereof.  
     The compounds are selective KDR Kinase and/or FGFr Kinase inhibitors and are of use in the prophylaxis and treatment of disease states assoicated with angiogenesis.

[0001] This invention relates to substituted 5-cyano-2-aminopyrimidines,to processes for their preparation, to pharmaceutical compositionscontaining them, and to their use in medicine.

[0002] Angiogenesis, the growth of capillaries from existing bloodvessels, is an essential process in normal embryonic development, tissuerepair and some aspects of female reproductive function. It is alsoassociated with the development of several pathological disordersincluding solid tumour growth, metastasis, psoriasis and rheumatoidarthritis, as well as diabetic retinopathy and age related maculardegeneration [Folkman, Nature Medicine, (1995) 1, 27-310].

[0003] Several growth factors have been shown to mediate angiogenesisthrough alteration of vascular permeability, including vascularendothelial growth factor [VEGF; G. Breier et al., Trends in CellBiology, (1996), 6, 454-6], platelet derived growth factor (PDGF) andacidic and basic fibroblast growth factors (a & b FGF).

[0004] VEGF in dimeric form is a ligand that binds to two transmembranetyrosine kinase associated receptors, expressed exclusively onproliferating endothelial cells, KDR (Flk-1 in mice) also known asVEGFR-2, and Flt-1 also known as VEGFR-1. Binding of VEGF to KDR/Flk andFit leads to receptor dimerisation, kinase activation,autophosphorylation of the receptor and phosphorylation of intracellularsubstrates. An analogous series of events ensues after ligand occupancyof the more widely expressed tyrosine kinase associated FGFr receptor byaFGF or bFGF. Thus receptor tyrosine kinase activity initiates acellular signalling pathway leading to proliferation.

[0005] Antagonism of VEGF with antibody completely suppressesneovascularisation and growth of human rhabdomyosarcoma A673 speroids inathymic mice [Borgstrom et al, Cancer Res., (1996), 56 4032-4039].Suppression of bFGF gene expression by interferons a and b inhibitscapillary density in mice, leading to pancreatic eyelet tumoursuppression [Folkman et al, Proc. Natl. Acad.Sci. (1996), 93, 2002 andSingh et al Proc.Natl. Acad. Sci. (1995), 92, 10457). Other receptorassociated kinases such as PDGF and EGFr may also have some role inmediating angiogenesis.

[0006] We have now found a series of substituted5-cyano-2-aminopyrimidines which are potent and selective inhibitors ofreceptor tyrosine kinases involved in angiogenesis, especially KDRkinase and/or FGFr kinase. Selective inhibition of these kinases can beexpected to have a beneficial effect and the compounds are thus of usein the prophylaxis and treatment of disease states associated withangiogenesis, as described hereinafter.

[0007] Thus, according to one aspect of the invention, we provide acompound of formula (1):

[0008] wherein Ar is an optionally substituted aromatic orheteroaromatic group;

[0009] R¹ is a hydrogen atom or a straight or branched chain alkylgroup;

[0010] R² is a —X¹—R³ group where X¹ is a direct bond or a linker atomor group, and

[0011] R³ is an optionally substituted aliphatic, cycloaliphatic,heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;

[0012] and the salts, solvates, hydrates and N-oxides thereof.

[0013] When Ar in the compounds of formula (1) is an aromatic group itmay be for example an optionally substituted monocyclic or bicyclicfused ring C₆₋₁₂aromatic group, such as an optionally substitutedphenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenylgroup.

[0014] When the group Ar in compounds of the invention is aheteroaromatic group it may be an optionally substituted C₁₋₁₃heteroaromatic group, such as a C₁₋₉ heteroaromatic group, containingfor example one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms.

[0015] In general, the heteroaromatic group may be for example anoptionally substituted monocyclic heteroaromatic, or a bicyclic ortricyclic fused-ring heteroaromatic group. Monocyclic heteroaromaticgroups include for example five- or six-membered heteroaromatic groupscontaining one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include forexample nine- to thirteen-membered fused-ring heteroaromatic groupscontaining one, two or more heteroatoms selected from oxygen, sulphur ornitrogen atoms. Tricyclic heteroaromatic groups include for example ten-to fourteen-membered fused-ring heteroaromatic groups containing one,two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.The heteroaromatic group may be attached to the remainder of thecompound of formula (1) through any of its ring carbon atoms.

[0016] Particular examples of heteroaromatic groups represented by Arinclude optionally substituted pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,5-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, indazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl,cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydro-quinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

[0017] Optional substituents which may be present on the aromatic orheteroaromatic groups represented by Ar include one, two, three or moresubstituents, each represented by an atom or group —R⁴ or -Alk(R⁴)_(m),where R⁴ is a halogen atom, or an amino (—NH₂), substituted amino,nitro, cyano, hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl(—CO₂H), esterified carboxyl, thiol (—SH), substituted thiol, —COR⁵[where R⁵ is a -Alk(R⁴)_(m), aryl or heteroaryl group], —CSR⁵, —SO₃H,—SO₂R⁵, —SO₂NH₂, —SO₂NHR⁵, —SO₂N[R^(5]) ₂, —CONH₂, —CSNH₂, —CONHR⁵,—CSNHR⁵, —CON[R⁵]₂, —CSN[R^(5]) ₂, —NHSO₂H, —NHSO₂R⁵, —N[SO₂R⁵]₂,—NHSO₂NH₂, —NHSO₂NHR⁵,

[0018] —NHSO₂N[R⁵]₂, —NHCOR⁵, —NHCONH₂, —NHCONHR⁵, —NHCON[R⁵]₂, —NHCSR⁵,—NHC(O)OR⁵, or optionally substituted cycloaliphatic,heterocycloaliphatic, aryl or heteroaryl group; Alk is a straight orbranched C₁₋₆ alkylene, C₂₋₆ alkenylene or C₂₋₆ alkynylene chain,optionally interrupted by one, two or three —O— or —S— atoms or groupsselected from —S(O)—, —S(O)₂— or —N(R⁶)— [where R⁶ is a hydrogen atom ora straight or branched chain C₁₋₆ alkyl group]; and m is zero or aninteger 1, 2 or 3.

[0019] When in the group -Alk(R⁴)_(m) m is an integer 1, 2 or 3, it isto be understood that the substituent or substituents R⁴ may be presenton any suitable carbon atom in -Alk. Where more than one R⁴ substituentis present these may be the same or different and may be present on thesame or different atom in -Alk or in R⁴ as appropriate. Thus forexample, -Alk(R⁴)_(m) may represent a —CH(R⁴)₂ group, such as a—CH(OH)Ar¹ group where Ar¹ is an aryl or heteroaryl group as definedbelow. Clearly, when m is zero and no substituent R⁴ is present thealkylene, alkenylene or alkynylene chain represented by Alk becomes analkyl, alkenyl or alkynyl group.

[0020] When R⁴ is a substituted amino group it may be for example agroup —NHR⁵ [where R⁵ is as defined above] or a group —N[R^(5]) ₂wherein each R⁵ group is the same or different.

[0021] When R⁴ is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

[0022] When R⁴ is a substituted hydroxyl or substituted thiol group itmay be for example a group —OR⁵ or —SR⁵ respectively.

[0023] Esterified carboxyl groups represented by the group R⁴ includegroups of formula —CO₂AIk¹ wherein Alk¹ is a straight or branched,optionally substituted C₁₋₈ alkyl group such as a methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; aC₆₋₁₂arylC₁₋₈alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₂aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₂ aryloxyC₁₋₈alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substitutedC₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or a C₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyl-oxypropyl group. Optional substituentspresent on the Alk¹ group include R⁴ substituents described above.

[0024] When Alk is present in or as a substituent, it may be for examplea methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene,s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene,3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylenechain, optionally interrupted by one, two, or three —O— or —S—, atoms or—S(O)—, —S(O)₂— or —N(R⁶)— (where R⁶ is a hydrogen atom or a straight orbranched C₁₋₆alkyl group) groups.

[0025] When R⁴ is present in compounds of formula (1) as an optionallysubstituted cycloaliphatic group it may be an optionally substitutedC₃₋₁₀ cycloaliphatic group. Particular examples include optionallysubstituted C₃₋₁₀cycloalkyl, e.g. C₃₋₇cycloalkyl, or C₃₋₁₀cycloalkenyle.g. C₃₋₇cyclo-alkenyl groups.

[0026] Heterocycloaliphatic groups represented by R⁴ include thealiphatic or cycloaliphatic groups just described for R⁴ but with eachgroup additionally containing one, two, three or four heteroatoms orheteroatom-containing groups selected from —O— or —S— atoms or —N(R⁶),—C(O), —C(S)—, —S(O)— or —S(O₂)— groups.

[0027] Particular examples of R⁴ cycloaliphatic and heterocycloaliphaticgroups include optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl,2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl,3,5,-cyclohexadien-1-yl, tetrahydrofuranyl, pyrroline, e.g. 2- or3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl,imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g.2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-,2H-1,2- or 4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5-oxadiazinylgroups.

[0028] Optional substituents which may be present on R⁴ cycloaliphaticand heterocycloaliphatic groups include one, two, three or moresubstituents selected from halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, or hydroxyl, C₁₋₆alkoxy, e.g. methoxy orethoxy, thiol, C₁₋₆alkylthio, e.g. methylthio or ethylthio, hydroxy,C₁₋₆alkyl, e.g. hydroxymethyl, hydroxyethyl, —CN, —NO₂, —NHR⁵ or —N(R⁵)₂groups.

[0029] Aryl and heteroaryl groups represented by the groups R⁴, R⁵ orAr¹ include for example optionally substituted monocyclic or bicyclicC₆₋₁₂ aromatic groups, e.g. phenyl groups, or C₁₋₉ heteroaromatic groupssuch as those described above in relation to the group Ar. Optionalsubstituents which may be present on these groups include one, two orthree R^(4a) atoms or groups described below.

[0030] Particularly useful atoms or groups represented by R⁴,-Alk(R⁴)_(m) or R^(4a) as appropriate include fluorine, chlorine,bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl or ethyl,C₁₋₆alkylamino, e.g. methylamino or ethylamino, hydroxyC₁₋₆alkyl, e.g.hydroxymethyl or hydroxyethyl, hydroxyC₂₋₆alkoxy, e.g. 2-hydroxyethoxyor 3-hydroxyethoxy, C₁₋₆alkylthiol e.g. methylthiol or ethylthiol,C₁₋₆alkoxy, e.g. methoxy or ethoxy, C₅₋₇cycloalkoxy, e.g.cyclopentyloxy, haloC₁₋₆alkyl, e.g. trifluoromethyl, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, aminoC₁₋₆alkoxy,C₁₋₆alkylaminoC₁₋₆alkoxy, diC₁₋₆alkylaminoC₁₋₆alkoxy, imido, such asphthalimido or naphthalimido, e.g. 1,8-naphthalimido,1,1,3-trioxobenzo[d]thiazolidino, nitro, cyano, hydroxyl (—OH), formyl[HC(O)—], carboxyl (—CO₂H), —CO₂Alk¹ [where Alk¹ is as defined above],C₁₋₆ alkanoyl e.g. acetyl, thiol (—SH), thioC₁₋₆alkyl, e.g. thiomethylor thioethyl, —SC(NH₂+)NH₂, sulphonyl (—SO₃H), C₁₋₆alkylsulphonyl, e.g.methylsulphonyl, aminosulphonyl (—SO₂NH₂), C₁₋₆alkylaminosulphonyl, e.g.methylaminosulphonyl or ethylaminosulphonyl, C₁₋₆dialkylaminosulphonyl,e.g. dimethylaminosulphonyl or diethylaminosulphonyl,phenylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g.methylaminocarbonyl or ethylaminocarbonyl, C₁₋₆dialkylaminocarbonyl,e.g. dimethylaminocarbonyl or diethylaminocarbonyl, sulphonylamino(—NHSO₂H), C₁₋₆alkylsulphonylamino, e.g. methylsulphonylamino orethylsulphonylamino, C₁₋₆dialkylsulphonylamino, e.g.dimethylsulphonylamino or diethylsulphonylamino, optionally substitutedphenylsulphonylamino, e.g. 2-, 3- or 4-substituted phenylsulphonylaminosuch as 2-nitrophenylsulphonylamino, aminosulphonylamino (—NHSO₂NH₂),C₁₋₆alkylaminosulphonylamino, e.g. methylaminosulphonylamino orethylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, e.g.dimethylaminosulphonylamino or diethylaminosulphonylamino,phenylaminosulphonylamino, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,phenylaminocarbonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,optionally substituted phenylcarbonylamino, C₁₋₆alkanoylaminoC₁₋₆alkyl,e.g. acetylaminomethyl, C₁₋₆alkoxycarbonylamino, e.g.methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino,optionally substituted heteroC₃₋₆cycloalkyl, e.g. piperidinyl,piperazinyl, 4-(C₁₋₆alkyl)piperazinyl, e.g. 4-methylpiperazinyl,homopipeprazinyl, or morpholinyl, optionally substitutedheteroC₃₋₆cycloalkylC₁₋₆alkyl, e.g. piperidinylC₁₋₆alkyl,piperazinylC₁₋₆alkyl, 4-(C₁₋₆alkyl)piperazinylC₁₋₆alkyl, e.g.4-methylpiperazinylmethyl, or morpholinylC₁₋₆alkyl, optionallysubstituted heteroC₃₋₆cycloalkylC₁₋₆alkoxy, e.g. morpholinylC₁₋₆alkoxy,optionally substituted heteroC₃₋₆alkylC₁₋₆alkylamino, optionallysubstituted heteroC₃₋₆cycloalkylamino, tetrazolyl, optionallysubstituted imidazolyl, optionally substituted triazolyl, e.g.1,2,4-,1,2,3-, 1,3,4- or 1,2,5-triazolyl, optionally substitutedimidazolylC₁₋₆alkyl, optionally substituted imidazolylC₁₋₆alkoxy,optionally substituted triazolylC₁₋₆alkoxy, optionally substitutedimidazolylaminoC₁₋₆alkoxy, optionally substituted phenylamino,optionally substituted benzylamino, optionally substituted benzyloxy, oroptionally substituted pyridylmethylamino group.

[0031] Where desired, two R⁴ or -Alk(R⁴)_(m) substituents may be linkedtogether to form a cyclic group such as a cyclic ether, e.g. aC₂₋₆alkylenedioxy group such as ethylenedioxy.

[0032] It will be appreciated that where two or more R⁴, -Alk(R⁴)_(m) orR^(4a) substituents are present, these need not necessarily be the sameatoms and/or groups.

[0033] Especially useful R⁴, -Alk(R⁴)_(m) or R^(4a) substituents includefor example fluorine, chlorine, bromine or iodine atoms, or amethylamino, ethylamino, hydroxymethyl, hydroxyethyl, methylthiol,ethylthiol, methoxy, ethoxy, n-propoxy, 2-hydroxyethoxy,3-hydroxypropoxy, 4-hydroxybutoxy, 2-aminoethoxy, 3-aminopropoxy,2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy,3-(dimethyl-amino)propoxy, cyclopentyloxy, cyclohexyl, cyclohexylamino,2-hydroxycyclohexylamino, trifluoromethyl, trifluoromethoxy,methylamino, ethylamino, amino (—NH)₂, aminomethyl, aminoethyl,dimethylamino, diethylamino, ethyl(methyl) amino, propyl(methyl)amino,2-hydroxyethylamino, 3-hydroxypropylamino, 4-hydroxybutylamino,2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino,2-(methylamino)ethylamino, 2-(ethylamino)ethylamino,2-(i-propylamino)ethylamino, 3-(i-propylamino)propylamino,2-(dimethylamino)ethylamino, 3-(dimethylamino)propylamino,2-(diethylamino)ethylamino, 3-(diethylamino)propylamino,2-(methylamino)ethyl(methyl)amino, 3-(methylamino)propyl(methyl)amino,2-(dimethylamino)ethyl(methyl)amino, 2-(dimethylamino)ethyl(ethyl)amino,dimethylaminoethoxy, nitro, cyano, hydroxyl (—OH), formyl [HC(O)-],carboxyl (—CO₂H), —CH₂CO₂H, —OCH₂CO₂H, —CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₃,—CH₂CO₂CH₂CH₃, —CH₂CO₂CH₂phenyl, t-butoxycarbonylmethoxy, acetyl,phenacetyl thio (—SH), thiomethyl, thioethyl, —SC(NH)NH₂, sulphonyl(—SO₂H), methylsulphonyl, methylaminosulphonyl, ethylaminosulphonyl,dimethylaminosulphonyl, diethylaminosulphonyl, carboxamido (—CONH₂),methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl,diethylaminocarbonyl, methylaminocarbonylmethyl, —NHC(S)NH₂,sulphonylamino (—NHSO₂H), methylsulphonylamino ethylsulphonylamino,dimethylsulphonylamino, diethylsulphonylamino, sulphonylamino(—NHSO₂NH₂), methylaminosulphonylamino, ethylaminosulphonylamino,dimethylaminosulphonylamino, diethylaminosulphonylamino,methylaminocarbonylamino, ethylaminocarbonylamino,dimethylaminocarbonylamino diethylaminocarbonylamino, acetylamino,phenylcarbonylamino, aminomethylcarbonylamino, acetylaminomethyl,methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino,pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl,4-methylpiperazinylC₁₋₆alkylphenylcarbonylamino, homopiperazinyl,morpholinyl, pyrrolidinylC₁₋₆alkyl, piperidinylC₁₋₆alkyl,piperazinylC₁₋₆alkyl, 4-(C₁₋₆alkyl)piperazinylC₁₋₆alkyl,morpholinylC₁₋₆alkyl, morpholinoethoxy, 2-pyrrolidinylethylamino,2-(1-methylpyrrolidinyl)ethylamino, 1-ethylpyrrolidinylmethylamino,piperidinylamino, 1-benzylpiperidinylamino, imidazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,5-triazolyl,C₁₋₆alkylimidazolylC₁₋₆alkyl, imidazolylC₁₋₆alkoxy, triazolylC₁₋₆alkyl,triazolylC₁₋₆alkoxy, imidazolylC₁₋₆alkyl such as imidazlylmethyl orimidazolylethyl, 4-(methoxy)phenylamino, 4-(3-hydroxypropyl)phenylamino,benzylamino, benzyloxy or pyridiylmethylamino group.

[0034] In the compounds of formula (1), when the group R¹ or the groupR⁶ [when present as —N(R⁶)—] is a straight or branched chain alkyl groupit may be for example a C₁₋₆ straight or branched chain alkyl group suchas a methyl, ethyl, n-propyl or isopropyl group.

[0035] Linker atoms represented by X¹ when present in compounds offormula (1) include —O— or —S— atoms. When X¹ is a linker group it maybe for example a —C(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁷)— [where R⁷is ahydrogen atom or a C₁₋₆ alkyl, e.g. methyl or ethyl, group], —C(R⁷)₂—,—CON(R⁷)—, —OC(O)N(R⁷)—, —CSN(R⁷)—, —N(R⁷)CO—, —N(R⁷)C(O)O—, —N(R⁷)CS—,—SON(R⁷), —SO₂N(R⁷), —N(R⁷)SO₂—, —N(R⁷)CON(R⁷)—, —N(R⁷)CSN(R⁷)—,—N(R⁷)SON(R⁷)— or —N(R⁷)SO₂N(R⁷) group.

[0036] In the compounds of formula (1), when R² is —X¹R³ and R³ is anoptionally substituted aliphatic group, R³ may be an optionallysubstituted C₁₋₁₀ aliphatic group for example an optionally substitutedstraight or branched chain C₁₋₆ alkyl, e.g. C₁₋₃alkyl, C₂₋₆ alkenyl,e.g. C₂₋₄alkenyl, or C₂₋₆ alkynyl, e.g. C₂₋₄ alkynyl group. Each of saidgroups may be optionally interrupted by one or two heteroatoms orheteroatom-containing groups represented by X² [where X² is an atom orgroup as just described for X¹], to form an optionally substituted R³heteroaliphatic group.

[0037] Particular examples of aliphatic groups represented by R³ includeoptionally substituted —CH₃, —CH₂CH₃—(CH₂)₂CH₃, —CH(CH₃)₂, —C(CH₃)₃,—(CH₂)₃CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, —(CH₂)₄CH₃,—(CH₂)₅CH₃, —CHCH₂, —CHCHCH₃, —CH₂CHCH₂, —CHCHCH₂CH₃, —CH₂CHCHCH₃,—(CH₂)₂CHCH₂, —CCH, —CCCH₃, —CH₂CCH, —CCCH₂CH₃, —CH₂CCCH₃, or —(CH₂)₂CCHgroups. Where appropriate each of said groups may be optionallyinterrupted by one or two atoms and/or groups X² to form an optionallysubstituted heteroaliphatic group. Particular examples include—CH₂X²CH₃, —CH₂X²CH₂CH₃, —(CH₂)₂X²CH₃ and —(CH₂)₂X²CH₂CH₃ groups.

[0038] The optional substituents which may be present on these aliphaticand/or heteroaliphatic groups include one, two, three or moresubstituents selected from halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, or hydroxyl, C₁₋₆ alkoxy, e.g. methoxy orethoxy, thiol, C₁₋₆ alkylthio, e.g. methylthio or ethylthio, —SC(NH)NH₂,—CH₂C(NH)NH₂, amino, substituted amino or cyclic amino groups.

[0039] Substituted amino groups include for example groups of formulae—NR⁸R⁹ [where R⁸ is an optionally substituted C₁₋₆alkyl, C₂₋₆alkenyl orC₂₋₆alkynyl group optionally interrupted by one or two heteroatoms orheteroatom-containing groups represented by X³ (where X³ is an atom orgroup as described above for X¹) and R⁹ is a hydrogen atom or is a groupas just defined for R⁸], —N(R⁹)COR⁸, —N(R⁹)CSR⁸, —N(R⁹)SOR⁸,—N(R⁹)SO₂R⁸, —N(R⁹)CONH₂, —N(R⁹)CONR⁸R⁹, —N(R⁹)C(O)OR⁸, —N(R⁹)C(NH)NH₂,—N(R⁹)C(NH)NR⁸NR⁹, —N(R⁹)CSNH₂, —N(R⁹)CSNR⁸R⁹, —N(R⁹)SONH₂,—N(R⁹)SONR⁸R⁹, —N(R⁹)SONH₂, —N(R⁹)SO₂NH₂, —N(R⁹)SONR⁸R⁹ or —N(R⁹)Cyc¹[where Cyc¹ is an optionally substituted C₃₋₇ monocyclic carbocyclicgroup optionally containing one or more —O— or —S— atoms or —N(R⁶)—,—C(O)—, —C(S)—, —S(O)— or —S(O₂)— groups].

[0040] Cyclic amino substituents which may be present on R³ aliphatic orheteroaliphatic groups include groups of formula —NHet¹, where —NHet¹ isan optionally substituted C₃₋₇ cyclic amino group optionally containingone or more other heteroatoms or heteroatom containing groups selectedfrom —O— or —S— atoms or —N(R⁶)—, —C(O), —C(S)—, —S(O)— or —S(O₂)—groups.

[0041] Particular examples of amino, substituted amino and cyclic aminogroups include —NH₂, methylamino, ethylamino, dimethylamino,diethylamino, —NHCyc¹ where Cyc¹ is an optionally substitutedcyclopentyl, cyclohexyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group, or—NHet¹ where —NHet¹ is an optionally substituted pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl orthiomorpholinyl group. Optional substituents which may be present onthese groups and substituted and cyclic amino groups in general includeone, two or three halogen atoms, e.g. fluorine, chlorine, bromine oriodine atoms, or C₁₋₄alkyl, e.g. methyl or ethyl, —NH2-, —NHCH3-,—N(CH₃)₂, hydroxyl, or C₁₋₄alkoxy, e.g. methoxy or ethoxy groups.

[0042] When R³ is present in compounds of formula (1) as an optionallysubstituted cycloaliphatic group it may be an optionally substitutedC₃₋₁₀ cycloaliphatic group. Particular examples include optionallysubstituted C₃₋₁₀cycloalkyl, e.g. C₃₋₇cycloalkyl, or C₃₋₁₀cycloalkenyle.g. C₃₋₇cycloalkenyl groups.

[0043] Heteroaliphatic or heterocycloaliphatic groups represented by R³include the aliphatic or cycloaliphatic groups just described for R³ butwith each group additionally containing one, two, three or fourheteroatoms or heteroatom-containing groups represented by X², where X²is as described above.

[0044] Particular examples of R³ cycloaliphatic and heterocycloaliphaticgroups include optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl,2-cyclopenten-1-yl, 3-cyclo-penten-1-yl, 2,4-cyclopentadien-1-yl,3,5,-cyclohexadien-1-yl, tetrahydro-furanyl, pyhrroline, e.g. 2- or3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl,imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g.2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-,2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5-oxadiazinylgroups.

[0045] Optional substituents which may be present on R³ cycloaliphaticand heterocycloaliphatic groups include C₁₋₆alkyl groups and thoseoptional substituents described above for R³ when it is an aliphaticgroup. The heterocycloaliphatic groups may be attached to the remainderof the molecule of formula (1) through any appropriate ring carbon orheteroatom.

[0046] When R³ is present as an aromatic or heteroaromatic group incompounds of formula (1) it may be for example an optionally substitutedaromatic or heteroaromatic group as described above in relation to thegroup Ar. Optional substituents which may be present on these aromaticor heteroaromatic groups include one, two or three R^(4b) or-Alk(R^(4b))_(m) substituents where R^(4b) is an atom or group asdescribed above for R⁴, and Alk and m are as described previously.Particular substituents include optionally substituted C₁₋₆alkyl groups[wherein the optional substituents include one, two or three of thoseoptional substituents described above for R³ when it is an aliphaticgroup and halogen atoms, e.g. fluorine, chlorine, bromine or iodineatoms or hydroxyl, C₁₋₆alkoxy, e.g. methoxy or ethoxy, thiol,C₁₋₆alkylthio, e.g. methylthio or ethylthio, —SC(NH)NH₂, —CH₂C(NH)NH₂,amino, substituted amino or cyclic amino groups as described above forthe optinoal substituents on aliphatic R₃ groups.

[0047] The presence of certain substituents in the compounds of formula(1) may enable salts of the compounds to be formed. Suitable saltsinclude pharmaceutically acceptable salts, for example acid additionsalts derived from inorganic or organic acids, and salts derived frominorganic and organic bases.

[0048] Acid addition salts include hydrochlorides, hydrobromides,hydroiodides, alkylsulphonates, e.g. methanesulphonates,ethanesulphonates, or isethionates, arylsulphonates, e.g.p-toluenesulphonates, besylates or napsylates, phosphates, sulphates,hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates,maleates, fumarates, malonates, succinates, lactates, oxalates,tartrates and benzoates.

[0049] Salts derived from inorganic or organic bases include alkalimetal salts such as sodium or potassium salts, alkaline earth metalsalts such as magnesium or calcium salts, and organic amine salts suchas morpholine, piperidine, piperazine, dimethylamine or diethylaminesalts.

[0050] Particularity useful salts of compounds according to theinvention include pharmaceutically acceptable salts, especially acidaddition pharmaceutically acceptable salts.

[0051] It will be appreciated that depending on the nature of the groupAr and the substituent R², the compounds of formula (1) may exist astautomers and/or geometrical isomers and/or may have one or more chiralcentres so that enantiomers or diasteromers may exist. It is to beunderstood that the invention extends to all such tautomers and isomersof the compounds of formula (1), and to mixtures thereof, includingracemates.

[0052] In the compounds according to the invention the aromatic grouprepresented by Ar is preferably a substituted phenyl group. Theheteroaromatic group represented by Ar is preferably a substituted five-or six-membered monocyclic heteroaromatic group or a nine- orten-membered fused-ring heteroaromatic group, each of said groupscontaining one or two oxygen, sulphur and/or nitrogen atoms.Particularly useful groups of these types include substituted pyridyl,indolyl, benzimidazolyl, indazolyl, benzothiazolyl, quinolyl,isoquinolyl and benzoxazolyl groups. Substituted quinolyl, indazolyl orbenzothiazolyl groups are especially useful. The substituent(s) presenton any of the above-mentioned preferred Ar groups may be any of those—R⁴ or -Alk(R⁴)_(m) atoms or groups, particularly one, two or three —R⁴and/or -Alk(R⁴)_(m) atoms or groups, generally or particularly describedabove and hereinafter in the Examples. Particularly useful substituentsare those which contain one or more basic centres, as describedhereinafter. In one preference, at least one —R⁴ or -Alk(R⁴)_(m)substituent will contain a basic centre.

[0053] In general in compounds of the invention R¹ is preferably ahydrogen atom.

[0054] In one general preference, R² in compounds of formula (1) is agroup —X¹R³ in which X¹ is a direct bond. In these compounds R³ ispreferably an optionally substituted aromatic group or an optionallysubstituted heteroaromatic group containing one or two ring oxygen,sulphur and/or nitrogen atoms and is especially a monocyclicheteroaromatic group. Thus in particular R³ may be an optionallysubstituted phenyl, thienyl, thiazolyl, indolyl or pyridyl group. Thepyridyl group may in general be attached to the remainder of thecompound of formula (1) through any available ring carbon atom and is inrelation to that carbon atom, a 2-, 3- or 4-pyridyl group. Substituted3-pyridyl groups are especially useful. Substituents which may bepresent on these R³ aromatic and heteroaromatic groups include one, twoor three —R^(4b) or -Alk(R^(4b))_(m) substituents as described ingeneral and in particular above and hereinafter in the Examples. In onepreference, at least one —R^(4b) or -Alk(R^(4b))_(m) substituent willcontain a basic centre as described hereinafter.

[0055] A particularly useful group of compounds according to theinvention has the formula (1) wherein Ar is a substituted phenyl,six-membered monocyclic heteroaromatic group or nine- or ten-memberedfused-ring heteroaromatic group, each of said groups containing one ortwo oxygen, sulphur and/or nitrogen atoms; R¹ is a hydrogen atom and R²is an optionally substituted phenyl, thienyl, thiazolyl or monocyclic orbicyclic heteroaromatic group containing one or two oxygen, sulphurand/or nitrogen atoms.

[0056] In compounds of this type, Ar is especially a substituted phenyl,pyridyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl,isoquinolyl or benzoxazolyl group. Substituted phenyl groups areparticularly useful. The group R² is preferably an optionallysubstituted thienyl, phenyl, indolyl or pyridyl group.

[0057] The substituents which may be present on Ar or R² groups of thesetypes include one, two or three of those —R⁴, -Alk(R⁴)_(m) —R^(4b)and/or -Alk(R^(4b))_(m) substituents generally and particularlydescribed above in relation to compounds of formula (1), especiallysubstituents which contain one or more basic centres. Particularlyuseful substituents containing basic centres include nitrogen containinggroups such as amino, substituted amino and cyclic amino groups, asdescribed above in relation to optional substituents present on R³aliphatic groups, optionally substituted and nitrogen-containingheteroaromatic groups, particularly five- or six-memberednitrogen-containing monocyclic heteroaromatic groups such as optionallysubstituted imidazolyl groups.

[0058] Particular groups containing basic centres include—X^(1a)(Alk^(a))_(p)NR^(7a)R^(7b) (where X^(1a) is a direct bond or alinker atom or group as defined above for X¹, Alk^(a) is as definedabove for Alk, p is zero or an integer 1) and R^(7a) and R^(7b) whichmay be the same or different is each a hydrogen atom or a straight orbranched C₁₋₆alkyl group, —X^(1a)(Alk^(a))_(p)NHet¹ (where —NHet¹ is asdefined above) and —X^(1a)(Alk^(a))_(p)Ar² (where Ar² is a nitrogencontaining heteroaromatic group as described above for Ar). In thesegroups, NR^(7a)R^(7b) may in particular be —NHCH₃, —N(CH₃)₂, —NHCH₂CH₃,—N(CH₃)(CH₂CH₃), or —N(CH₂CH₃)₂, —NHet¹ may in particular be optionallysubstituted pyrrolidinyl, piperidinyl, imidazolidinyl, piperazinyl,morpholinyl, thiomorpholinyl or pyrazolidinyl; Ar2 may in particular beoptionally substituted imidazolyl. X^(1a) when present may in particularbe an oxygen atom or a —NH— group.

[0059] Especially useful —R^(4b) and -Alk(R^(4b))_(m) substituents incompounds of the invention include —NH₂, —(CH₂)₂NH₂, —C(CH₃)₂NH₂,—C(CH₃)₂NHCH₃, —C(CH₃)₂N(CH₃)₂, —CH₂N(CH₂CH₃)₂, —CONH(CH₂)₂N(CH₂CH₃)₂,—C(CH₃)₂—pyrrolidinyl, dimethylaminopyrrolidinyl, imidazolyl,imidazolylmethyl, imidazolylethyl and piperidinylethyl groups.Particularly useful —R⁴ and -Alk(R⁴)_(m) substituents include fluorineand chlorine atoms and methyl, ethyl, methoxy, —CF₃, —CH₂F₂, —CH₂F, —OH,—OCF₃, —OCHF₃, —OCHF₂, —OCH₂F, —NO₂, —CN, —NH₂, —NHCH₃, —N(CH₃)₂,Ar^(2a) where Ar^(2a) is imidazolyl, C₁₋₃alkylimidazolyl, triazolyl orC₁₋₃alkyl-triazolyl, —C₁₋₃alkylAr^(2a), —OC₁₋₃alkylAr^(2a), —NHet^(1a),where —NHet^(1a) is piperidinyl, C₁₋₃alkylpiperidinyl, morpholinyl,C₁₋₃alkylmorpholinyl, pyrrolidinyl, C₁₋₃alkylpyrrolidinyl, piperazinyl,C₁₋₃alkylpiperazinyl, imidazolidinyl, C₁₋₃alkylimiazolidinyl,pyrazolidinyl or C₁₋₃alkylpyrazolidinyl, —C₁₋₃alkylNHet^(1a),—OC₁₋₃alkylNHet^(1a), and —NHCOAr³ where Ar³ is phenyl optionallysubstituted by Ar^(2a), —C₁₋₃alkylAr^(2a), —OC₁₋₃alkylAr^(2a), —NHet¹,—C₁₋₃alkylNHet¹ and —OC₁₋₃alkylNHet¹.

[0060] In the above preferred groups the term triazolyl is intended tomean all possible isomers as described above in relation to the group Arand especially includes 1,2,3- and 1,2,4-triazolyl groups.

[0061] Particularly useful compounds of the invention include:

[0062] 5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;

[0063]5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylphenyl)pyrimidine-2-amine;

[0064]5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;

[0065]5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;

[0066]5-Cyano-4-[2-(3(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol-5-yl)pyrimidine-2-amine;

[0067]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine;

[0068]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;

[0069]5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylpyrimidine-2-amine;

[0070]5-Cyano-4-phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}-pyrimidine-2-amine;

[0071]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4(1,2,3-triazol-1-yl)-phenyl]pyrimidine-2-amine;

[0072]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine;

[0073]N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide;

[0074]4-[3-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-methylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amino;

[0075]5-Cyano-4-[4-(imiadzol-1-yl)methyl]phenyl-N-(3,4,5-trimethoxyphenyl)-pyrimidine-2-amino;

[0076] and the salts, solvates, hydrates and N-oxides thereof.

[0077] Especially useful compounds according to the invention include:

[0078]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine;

[0079]5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4-(1-dimethylamino-1-methylethyl)phenyl]pyrimidine-2-amine;

[0080]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine;

[0081]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]phenyl}pyrimidine-2-amine;

[0082]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine;

[0083] 4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;

[0084] 4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;

[0085] 5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine;

[0086]5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl)pyrimidine-2-amine;

[0087] 4-(4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrimidine-2-amine;

[0088] and the salts, solvates, hydrates and N-oxides thereof.

[0089] Compounds according to the invention are potent and selectiveinhibitors of KDR and/or FGFr kinases as demonstrated by differentialinhibition of these enzymes when compared to inhibition of other proteinkinases such as EGFr kinase, p56^(lck) kinase, ZAP-70 kinase, proteinkinase C, Csk kinase and p59^(fyn) kinase. The ability of the compoundsto act in this way may be simply determined by employing tests such asthose described in the Examples hereinafter.

[0090] The compounds according to the invention are thus of particularuse in the prophylaxis and treatment of diseases in which inappropriateKDR kinase action plays a role, for example in disease states associatedwith angiogenesis. The compounds are then of use for example in theprophylaxis and treatment of cancer, prosiasis, rheumatoid arthritis,Kaposi's Sarcoma, ischemic heart disease, atherosclerosis and occulardiseases, such as diabetic retinopathy, involving retinal vesslproliferation and the invention is to be understood to extend to suchuses and to the use of a compound of formula (1) in the preparation of amedicament for the prophylaxis and teatment of such diseases.

[0091] For the prophylaxis or treatment of disease the compoundsaccording to the invention may be administered as pharmaceuticalcompositions, and according to a further aspect of the invention weprovide a pharmaceutical composition which comprises a compound offormula (1) together with one or more pharmaceutically acceptablecarriers, excipients or diluents.

[0092] Pharmaceutical compositions according to the invention may take aform suitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsulation.

[0093] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

[0094] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0095] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0096] The compounds for formula (1) may be formulated for parenteraladministration by injection, including bolus injection or infusion orparticle mediated injection. Formulations for injection may be presentedin unit dosage form, e.g. in glass ampoule or multi dose containers,e.g. glass vials or a device containing a compressed gas such as heliumfor particle mediated administration. The compositions for bolusinjection or infusion may take such forms as suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. For particle mediated administration the complex may becoated on particles such as microscopic gold particles.

[0097] In addition to the formulations described above, the compounds offormula (1) may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation or byintramuscular injection. Where desired, the compounds according to theinvention may also be conjugated to a polymer, e.g. a naturally occuringpolymer such as albumin, to prolong the half life of the compounds whenin use. Such conjugates may be formulated and delivered as describedabove.

[0098] For nasal administration or administration by inhalation, thecompounds for use according to the present invention are convenientlydelivered in the form of an aerosol spray presentation for pressurisedpacks or a nebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichloro-fluoromethane,dichlorotetrafluoroethane, carbon dioxide orother suitable gas ormixture of gases.

[0099] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack or dispensing device may beaccompanied by instructions for administration.

[0100] The quantity of a compound of the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen, and the condition of the patient to be treated.In general, however, daily dosages may range from around 100 ng/kg to100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral orbuccal administration, from around long/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufation.

[0101] The compounds of the invention may be prepared by a number ofprocesses as generally described below and more specifically in theExamples hereinafter. In the following process description, the symbolsR¹, R², Alk, Alk¹ and Ar when used in the text or formulae depicted areto be understood to represent those groups described above in relationto formula (1) unless otherwise indicated. In the reactions describedbelow, it may be necessary to protect reactive functional groups, forexample hydroxy, amino, thio or carboxy groups, where these are desiredin the final product, to avoid their unwanted participation in thereactions. Conventional protecting groups may be used in accordance withstandard practice [see, for example, Green, T. W. in “Protective Groupsin Organic Synthesis”, John Wiley and Sons, (1991)]. In some instances,deprotection may be the final step in the synthesis of a compound offormula (1) and the processes according to the invention describedhereinafter are to be understood to extend to such removal of protectinggroups.

[0102] Thus according to a further aspect of the invention, a compoundof formula (1) may be prepared by reaction of a guanidine of formula(2):

Ar—N(R¹)C(═NH)NH₂  (2)

[0103] or a salt thereof

[0104] with an enaminone of formula (3):

R²COC(CN)CHN(R¹⁰)(R¹¹)  (3)

[0105] where R¹⁰ and R¹¹, which may be the same or different is each aC₁₋₆ alkyl group.

[0106] The reaction may be performed in a solvent, for example a proticsolvent such as an alcohol, e.g. ethanol, methoxyethanol or propan-2-ol,optionally in the presence of a base e.g. an alkali metal base, such assodium hydroxide or potassium carbonate, at an elevated temperature,e.g. the reflux temperature.

[0107] Salts of the compounds of formula (2) include acid salts such asinorganic acid salts e.g. hydrochlorides or nitrates.

[0108] Intermediate guanidines of formula (2) may be prepared byreaction of the corresponding amine ArNH₂ with cyanamide at an elevatedtemperature. The reaction may be performed in a solvent such as ethanolat an elevated temperature, e.g. up to the reflux temperature. Where itis desired to obtain a salt of a guanidine of formula (2), the reactionmay be performed in the presence of a concentrated acid, e.g.hydrochloric or nitric acid.

[0109] The amines ArNH₂ are either known compounds or may be obtained byconventional procedures, for example by hydrogenation of thecorresponding nitro derivatives using for example hydrogen in thepresence of a metal catalyst in a suitable solvent, for example as moreparticularly described in the interconversion reactions discussed below.The nitrobenzenes for this particular reaction are either knowncompounds or may be prepared using similar methods to those used for thepreparation of the known compounds.

[0110] Intermediate enaminones of formula (3) are either known compoundsor may be prepared by reaction of an acetyl derivative R²COCH₂CN with anacetal (R¹⁰)(R¹¹)NCH(OR¹²)₂ (where R¹² is a C₁₋₆alkyl group such as amethyl or ethyl group) at an elevated temperature. The startingmaterials for this reaction are either known compounds or may beprepared by methods analogous to those used for the preparation of theknown compounds.

[0111] One particularly useful method for the preparation of acetylderivatives R²COCH₂CN involves treating a corresponding isoxazole offormula (4):

[0112] with a base such as an alkoxide, e.g. sodium ethoxide, in asolvent such as an alcohol, e.g.ethanol, at ambient temperature.Intermediate isoxazoles of formula (4) may be obtained by reaction ofthe corresponding aminopropenone (R²COCHCHN(R¹⁰)(R¹¹) withhydroxyl-amine in a solvent such as an alcohol, e.g. MeOH at ambienttemperature. The aminopropenone starting material for this rection maybe obtained by reaction of the corresponding methyl ketone R²COCH₃ withan acetal (R¹⁰)(R¹¹)NCH(OR¹²)₂ as described above.

[0113] In another process according to the invention, a compound offormula (1) may be prepared by displacement of a chlorine atom in apyrimidine of formula (5):

[0114] with an amine ArNH₂.

[0115] The reaction may be performed at an elevated temperature, forexample the reflux temperature, where necessary in the presence of asolvent, for example an alcohol, such as 2-ethoxyethanol or isopopanol,a cyclic ether, e.g. dioxane or a substituted amide such asdimethylformamide, optionally in the presence of a base, for example anorganic amine such as pyridine.

[0116] Intermediate pyrimidines of formula (5) may be obtained byreaction of a corresponding pyrimidine of formula (6):

[0117] with phosphorous oxychloride optionally in a solvent such as asubstituted amide e.g. dimethylformamide at an elevated temperature, forexample the reflux temperature.

[0118] Intermediates of formula (6) may be prepared from thecorresponding amine

[0119] with sodium nitrite in an aqueous acid, e.g. aqueous sulphuricacid at around ambient temperature.

[0120] Amines of formula (7) may be prepared by reaction of an enaminoneof formula (3) with a guanidine salt, e.g. guanidine carbonate, asdescribed above for the preparation of compounds of formula (1).

[0121] Compounds of formula (1) may also be prepared by interconversionof other compounds of formula (1) and it is to be understood that theinvention extends to such interconversion processes. Thus, for example,standard substitution approaches employing for example alkylation,arylation, heteroarylation, acylation, thioacylation, sulphonylation,formylation or coupling reactions may be used to add new substitutentsto and/or extend existing substituents in compounds of formula (1).Alternatively existing substituents in compounds of formula (1) may bemodified by for example oxidation, reduction or cleavage reactions toyield other compounds of formula (1).

[0122] The following describes in general terms a number of approacheswhich can be employed to modify existing Ar and/or R² groups incompounds of formula (1). It will be appreciated that each of thesereactions will only be possible where an appropriate functional groupexists in a compound of formula (1).

[0123] Where desired, these reactions may also be performed onintermediates to compounds of formula (1), for example in thepreparation of intermediate amines, ArNH₂ or acetyl derivativesR²COCH₂CN, and the description which follows is intended to apply tothese intermediates even though only a compound of formula (1) ismentioned.

[0124] Thus, for example alkylation, arylation or heteroarylation of acompound of formula (1) may be achieved by reaction of the compound witha reagent AlkL or Ar³L, where Alk is an alkyl group and Ar³ is an arylor heteroaryl group as defined above in relation to compounds of formula(1) and L is a leaving atom or group such as a halogen atom, e.g. achlorine or bromine atom, or a sulphonyloxy group, e.g. anarylsulphonyloxy group such as a p-toluenesulphonyloxy group.

[0125] The alkylation, arylation or heteroarylation reaction may becarried out in the presence of a base, e.g. an inorganic base such as acarbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g.potassium t-butoxide, ora hydride, e.g. sodium hydride, in a dipolaraprotic solvent such as an amide, e.g. a substituted amide such asdimethylformamide or an ether, e.g. a cyclic ether such astetrahydrofuran, at around 0° C. to around 40° C.

[0126] In a variation of this process the leaving group L may bealternatively part of the compound of formula (1) and the reactionperformed with an appropriate nucleophilic reagent at an elevatedtemperature. Particular nucleophilic reagents include cyclic amines,such as piperazine or imidazole. Where appropriate the reaction may beperformed in a solvent such as an aprotic solvent, e.g. a substitutedamide such as dimethylformamide.

[0127] In another general example of an interconversion process, acompound of formula (1) may be acylated orthioacylated. The reaction maybe performed for example with an acyl halide or anhydride in thepresence of a base, such as a tertiary amine e.g. triethylamine in asolvent such as a halogenated hydrocarbon, e.g. dichloromethane orchloroform at for example ambient temperature, or by reaction with athioester in an inert solvent such as tetrahydrofuran at a lowtemperature such as around 0° C. Alternatively, the reacton may beperformed with an acid, in the presence of a condensing agent, forexample a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,advantageously in the presence of a catalyst such as a N-hydroxycompound, e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole in thepresence of a base, e.g. a cyclic amine such as N-methylmorpholine. Thereaction is particularly suitable for use with compounds of formula (1)containing primary or secondary amino groups.

[0128] In a further general example of an interconversion process, acompound of formula (1) may be formylated, for example by reaction ofthe compound with a mixed anhydride HCOOCOCH₃ or with a mixture offormic acid and acetic anhydride.

[0129] Compounds of formula (1) may be prepared in another generalinterconversion reaction by sulphonylation, for example by reaction ofthe compound with a reagent AlkS(O)₂L, or Ar2S(O)₂L in the presence of abase, for example an inorganic base such as sodium hydride in a solventsuch as an amide, e.g. a substituted amide such as dimethylformamide atfor example ambient temperature. The reaction may in particular beperformed with compounds of formula (1) possessing a primary orsecondary amino group.

[0130] In further examples of interconversion reactions according to theinvention compounds of formula (1) may be prepared from other compoundsof formula (1) by modification of existing functional groups in thelatter.

[0131] Thus in one example, estergroups —CO₂Alk¹ in compounds of formula(1) may be converted to the corresponding acid [—CO₂H] by acid- orbase-catalysed hydrolysis or by catalytic hydrogenation depending on thenature of the group Alk¹. Acid- or base-catalysed hydrolysis may beachieved for example by treatment with an organic or inorganic acid,e.g. TFA acid in an aqueous solvent or a mineral acid such ashydrochloric acid in a solvent such as dioxan or an alkali metalhydroxide, e.g. lithium hydroxide in an aqueous alcohol or ether e.g.aqueous MeOH or tetrahydrofuran,. Catalytic hydrogenation may be carriedout using for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon in a solvent such as anether, e.g. tetrahydrofuran or an alcohol, e.g. MeOH.

[0132] In a second example, —OAlk² [where Alk² represents an alkyl groupsuch as a methyl group] groups in compounds of formula (1) may becleaved to the corresponding alcohol —OH by reaction with borontribromide in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane at a low temperature, e.g. around −78° C.

[0133] In another example, alcohol —OH groups in compounds of formula(1) may be converted to a corresponding —OAlk or —OAr group by couplingwith a reagent AlkOH or ArOH in a solvent such as tetrahydrofuran in thepresence of a phosphine, e.g. triphenylphosphine and an activator suchas diethyl-, diisopropyl-, or dimethylazodicarboxylate.

[0134] Aminosulphonylamino [—NHSO₂NH₂] groups in compounds of formula(1) may be obtained, in another example, by reaction of a correspondingamine [—NH₂] with sulphamide in the presence of an organic base such aspyridine at an elevated temperature, e.g. the reflux temperature.

[0135] In another example of an interconversion process secondary aminegroups in compounds of formula (1) may be alkylated using an alcohol,e.g. ethanol and catalytic hydrogenation, employing for example hydrogenin the presence of a metal catalyst such as palladium on a support suchas carbon.

[0136] In a further example, amine [—NH₂] groups in compounds of formula(1) may be obtained by hydrolysis from a corresponding imide by reactionwith hydrazine in a solvent such as an alcohol, e.g. ethanol at ambienttemperature. In an altemative, amine groups may also be generated byreduction of the corresponding nitrile, for example using a reducingagent such as a borohydride, e.g. sodium borohydride or ceriumtrichloride. Alternatively, amine groups may be obtained by Ce^(IV)oxidation of the corresponding p-anisyl- or p-anisylmethylamines usingfor example ceric ammonium nitrate in a solvent such as acetonitrile.

[0137] In another example cyclic amino groups in compounds of formula(1) may be prepared by cyclisation of a corresponding compoundcontaining an amine [—NH₂] group with a reagent L¹AlkL² where L¹ and L²which may be the same or different is each a leaving atom or group asdescribed above L and may for example each be a halogen atom such as abromine atom. The reaction may advantageously be carried out in thepresence of a base e.g. an inorganic base such as potassium carbonate,at an elevated temperature.

[0138] In another example, a nitro [—NO₂] group may be reduced to anamine [—NH₂], for example by catalytic hydrogenation as just described,or by chemical reduction using for example a metal, e.g. tin or iron, inthe presence of an acid such as hydrochloric acid.

[0139] N-oxides of compounds of formula (1) may be prepared for exampleby oxidation of the corresponding nitrogen base using an oxidising agentsuch as hydrogen peroxide in the presence of an acid such as aceticacid, at an elevated temperature, for example around 70° C. to 80° C.,or alternatively by reaction with a peracid such as peracetic acid in asolvent, e.g. dichloromethane, at ambient temperature.

[0140] Where salts of compounds of formula (1) are desired, these may beprepared by conventional means, for example by reaction of a compound offormula (1) with an appropriate acid or base in a suitable solvent ormixture of solvents, e.g. an organic solvent such as an ether, e.g.diethylether, or an alcohol, e.g. ethanol.

[0141] The following Examples illustrate the invention. In the Examplesall ¹Hnmr were run at 300 MHz unless specified otherwise. Alltemperatures are in ° C.

[0142] The following abbreviations are used: THF—tetrahydrofuran; DMF—dimethylformamide; DMSO—dimethylsulphoxide; TFA—trifluoroacetic acid;DIBAL-H—diisobutylaluminium hydride; MeOH—methanol.

Intermediate 1 4-[2-(1,2,3-Triazol-1-yl)ethoxyl]phenylguanidiniumnitrate

[0143] The title compound was prepared from4-[2-(1,2,3-triazol-1-yl)ethoxy]aniline (4.91 g, 24.07 mmol), cyanamide(1.56 g, 40.97 mmol) and concentrated HNO₃ (1.58 mL, 26.47 mmol) in amanner similar to the guanidine of Example 1 to give the desiredmaterial (4.7 g) as an off-white solid, m.p. >250°. δH (d⁶ DMSO) 9.33(1H, s), 8.20 (1H, s), 7.74 (1H, s), 7.17-7.14 (6H, m), 7.00-6.97 (2H,m), 4.79 (2H,t, J 4.95 Hz) and 4.41 (2H, t, J 4.95 Hz).

[0144] 4-[2-(1,2,3-Triazol-1-yl)ethoxy]aniline was prepared from4-[2-(1,2,3-triazol-1-yl)ethoxy] nitrobenzene (5.98 g, 25.5 mmol) and10% palladium on charcoal (1.5 g) in a manner similar to the anilineintermediate of Example 12 to give the desired material (4.91 g) as ayellow solid m.p. 141°. δH (CDCl₃) 7.69 (1H, d, J 0.5 Hz), 7.62 (1H, d J0.5 Hz), 6.65 (2H, d, J 5.8 Hz), 6.58 (2H, d, J 5.8 Hz), 4.71 (2H, t, J5.0 Hz), 4.24 (2H, t, J 5.0 Hz) and 3.43 (2H, s).

[0145] 4-[2-(1,2,3-Triazol-1-yl)ethoxy]nitrobenzene was prepared from4-[(2-p-toluenesulphonyloxy)ethoxy]nitrobenzene (10 g, 29.7 mmol) and1,2,3-triazole, sodium salt (2.46 mmol) in a manner similar to theanalogous reaction of Example 24 to give the desired material (2.25 g)as yellow solid, m.p. 123°. δH (d⁶DMSO) 8.21 (1H, s), 8.20 (2H, d, J 2.3Hz), 7.74 (1H, d, J 0.5 Hz), 7.14 (2H, d, J 2.4 Hz), 4.84 (2H, t, J 4.9Hz) and 4.57 (2H, t, J 4.9 Hz). The reaction also yielded4-[2-(1,2,3-triazol-2-yl)ethoxy]nitro-benzene (4.36 g) as a yellowsolid, m.p. 111°. δH (d⁶ DMSO) 8.17 (2H, d, J 9.3 Hz), 7.80 (2H, s),7.11 (2H, d, J 9.3 Hz), 4.86 (2H, t, J 4.8 Hz) and 4.64 (2H, t, J 4.8Hz).

Intermediate 2 4-[2-(1,2,3-Triazol-2-yl)ethoxy]phenylguanidinium nitrate

[0146] The title compound was prepared from4-[2-(1,2,3-triazol-2-yl)ethoxy]aniline (8.85 g,43.4 mmol), cyanamide(2.82 g, 73.78 mmol) and concentrated HNO3 (1.58 mL, 26.47 mmol) in amanner similar to the guanidine of Example 1 to give the desiredmaterial (7.95 g) as an off-white solid, m.p. >250°. δH (d⁶ DMSO) 9.32(1H, s), 7.80 (2H, s), 7.16-7.13 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H,t, J 4.95 mmol) and 4.41 (2H, t, J 4.95 mmol).

[0147]4-[2-(1,2,3-Triazol-2-yl)ethoxy]aniline was prepared from4-[2-(1,2,3-triazol-2-yl)ethoxy] nitrobenzene (10.5 g, 44.8 mmol) and10% palladium on charcoal (1.5 g) in a manner similar to the anilineintermediate of Example 12 to give the desired material (4.91 g) as ayellow solid m.p. 159°. δH (CDCl₃) 7.62 (2H, s), 6.73-6.58 (4H, m), 4.77(2H, t, J 5.8 Hz), 4.40 (2H, t, J 5.8 Hz) 3.43 (2H, s).

Intermediate 3 4-[1,2,4-Triazol-1-yl)ethoxy]phenylguanidinium nitrate

[0148] The title compound was prepared from4-[2-(1,2,4-triazol-1-yl)ethoxy]aniline (5.30 g, 25.9 mmol), cyanamide(1.86 g, 44.11 mmol) and concentrated HNO₃ (1.88 mL, 28.54 mmol) in amanner similar to the guanidine of Example 1 to give the desiredmaterial (6.62 g) as an off-white solid, m.p. 280-282°. δH (d⁶ DMSO)9.33 (1H, bs), 8.56 (1H, s), 7.97 (1H, s), 7.17 (4H, bs), 7.16-7.12 (2H,s), 6.98-6.94 (2H, m), 4.58 (2H, t, J 5.0 Hz) and 4.34 (2H, t, J 2.0Hz).

[0149] 4-[2-(1,2,4-Triazol-1-yl)ethoxy]aniline was prepared from4-[2-(1,2,4-triazol-1-yl)ethoxy] nitrobenzene (6.28 g, 26.8 mmol) and10% palladium on charcoal (0.5 g) in a manner similar to the anilineintermediate of Example 12 to give the desired material (5.31 g) as ayellow solid m.p. 85-86°. δH (CDCl₃) 8.21 (1H, s), 7.94 (1H, s),6.69-6.58 (4H, m), 4.51 (2H, t, J 5.0 Hz), 4.24 (2H, t, J 5.2 Hz) and3.45 (2H, bs).

[0150] 4-[2-(1,2,4-Triazol-1-yl)ethoxy]nitrobenzene was prepared from4-[(2-p-toluenesulphonyloxy)ethoxy]nitrobenzene (10 g, 30.7 mmol) and1,2,4-triazole, sodium salt (3.36 g, 36.8 mmol) in a manner similar tothe analogous reaction of Example 24 to give the desired material (6.45g) as yellow solid, m.p. 118-120°. δH (CDCl₃) 8.21-8.17 (3H, m), 7.97(1H, s), 6.93-6.90 (2H, m), 4.62 (2H, t, J 5.2 Hz) and 4.45 (2H,t, J 5.3Hz).

Intermediate 4 2-Cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one

[0151] 2-Hydroxy-2-pyridin-3-ylacrylonitrile, sodium salt (1.0 g, 5.95mmol) was dissolved in methanol (20 mL) and dimethylformamidediethylacetal (1.2 mL, 7.0 mmol) followed by 1 M hydrochloric acid indiethyl ether (5.95 mL) were added. The reaction was stirred at roomtemperature for 1.5 h and then concentrated under reduced pressure. Theresulting residue was subjected to column chromatography (silica 3%methanol in dichloromethane) to give the desired product (560 mg) asyellow solid. δH (CDCl3) 8.98 (1H, dd, J 2.3, 0.8 Hz), 8.69 (1H, dd,4.8, 1.6 Hz), 8.08 (1H, dt, J 7.9, 2.2 Hz), 7.98 (1H, s), 7.37-7.33 (1H,m), 3.50 (3H,s) and (3H, s).

[0152] 2-Hydroxy-2-pyridin-3-ylacrylonitrile was prepared by adding asolution of ethyl nicotinate (22.67 g, 0.15 mol) and acetonitrile (15.6mol, 0.3 mol) in toluene (100 mL) and DMF (25 mL) to a suspension ofsodium ethoxide (9.70 g, 0.143 mol) and the resulting mixture heated atreflux for 2 h with vigorous stirring. On cooling the reaction wasdiluted with ether (400 mL) and the resulting precipitate collected andwashed further with ether to give the desired material (20.1 g) whichwas used without purification.

EXAMPLE 1 5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0153] A mixture of 3,4,5-trimethoxyphenylguanidinium nitrate (1.44 g,5.0 mmol), 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.0 g, 5.0mmol) and sodium hydroxide (0.22 g, 5.5 mmol) in ethanol (20 ml) washeated at reflux for 18 h. On cooling the resulting precipitate wascollected by filtration, washed with water and diethyl ether, then driedto give the title compound (895 mg) as a green solid m.p. 246°. δH (d⁶DMSO) 10.37 (1H, br s), 8.93 (1H, s), 7.99 (2H, m), 7.60 (3H, m), 7.25(2H, m), 3.75 (6H, s) and 3.63 (3H, s).

[0154] The propenone used as starting material was prepared by refluxingbenzoylacetonitrile (4.50 g, 31.0 mmol) in dimethylformamidediethylacetal (20 ml) for 12 h. On cooling the resulting solid wascollected and washed with diethyl ether to give the desired product(4.50 g) as a beige solid m.p. 980°.

[0155] 3,4,5-Trimethoxyphenylguanidinium nitrate was prepared by heatinga solution of 3,4,5-trimethoxyaniline (5.49 g, 30.0 mmol), cyanamide[Aldrich, 50% solution in water w/v] (3.50 ml, 34.5 mmol) andconcentrated HNO₃ (2.1 ml, 30.0 mmol) in ethanol (30 ml). The solidwhich formed on cooling to room temperature was collected by filtration,washed with ethanol and dried to give the desired material (4.60 g) as agrey solid m.p. 187°.

EXAMPLE 25-Cyano-N-[4-(2-hydroxyethyl)phenyl]-4-methoxycarbonylphenylpyrimidine-2-amine

[0156] In a similar manner to the compound of Example 1, from4-(2-hydroxyethyl)phenylguanidinium nitrate (1.88 g, 7.75 mmol),1-(4-methoxycarbonylphenyl)-2-cyano-3-dimethylaminopropen-1-one (2.07 g,7.75 mmol) and sodium hydroxide (310 mg, 7.75 mmol) to give the titlecompound (2.40 g) as a yellow solid m.p. 194-196°. δH (d⁶ DMSO) 10.52(1H, br s), 8.96 (1H, s), 8.15 (2H, d, J 8.2 Hz), 8.04 (2H, d, J 8.2Hz), 7.63 (2H, d, J 7.9 Hz), 7.18 (2H, d, J 7.9 Hz), 4.61 (1H, t, J 5.1Hz), 3.90 (3H, s), 3.57 (2H, m), and 2.68 (2H, d, J 7.0 Hz).

[0157] The propenone used as starting material in the above process wasprepared in a similar manner to the analogous compound of Example 1, togive a yellow solid m.p. 118°.

[0158]4-(2-Hydroxyethyl)phenylguanidinium nitrate was prepared in asimilar manner to the guanidine of Example 1 as an off-white solid.

EXAMPLE 3 5-Cyano-4-(4-methoxycarbonylphenyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0159] In a similar manner to the compound of Example 1, from3,4,5-trimethoxy-phenylguanidinium nitrate (1.12 g, 3.88 mmol),2-cyano-1-(4-methoxycarbonylphenyl)-3-dimethylaminopropen-1-one (1.0 g,3.9 mmol) and sodium hydroxide (258 mg,3.88 mmol) to give the titlecompound (760 mg) as a yellow solid m.p.206-208°. δH (d⁶DMSO) 10.46 (1H,s), 8.97 (1H, s), 8.15 (4H, m), 7.23 (2H, br s), 3.89 (3H, s), 3.74(6H,s) and 3.62 (3H, s).

EXAMPLE45-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylphenyl)pyrimidine-2-amine

[0160] To a solution of the compound of Example 2 (750 mg, 2.0 mmol) inpyridine (10 ml) was added 4-toluenesulphonyl chloride (458 mg, 2.0mmol) and the mixture stirred at ambient temperature for 2.5 h. Thereaction was diluted with dichloromethane (50 ml), washed with 1Mhydrochloric acid (2×50 ml) followed by saturated Na₂CO₃ (1×25 ml),dried (MgSO₄) and then concentrated under reduced pressure. The residuewas subjected to column chromatography (silica gel; 5%methanol-dichloromethane) to give the desired tosylate (600 mg) as ayellow solid. This material was dissolved in dry DMF (15 ml) containingimidazole (272 mg, 4.0 mmol) and the resulting mixture was stirred undera nitrogen atmosphere at 80° for 6 h. To the reaction was addedsaturated brine (150 ml) and 2M NaOH (10 ml) and this was extracted withdichloromethane (1×100 ml). The organic phase was dried (MgSO₄) andconcentrated under reduced pressure. The residue was recrystallised fromethyl acetate/propan-2-ol (10:1) to give the title compound (185 mg) asa pale yellow solid m.p. 216-218°. δH (d⁶ DMSO) 10.55 (1H, br s), 8.97(1H, s), 8.15 (2H, d, J 8.0 Hz), 8.04 (2H, d, J 8.0 Hz), 7.64 (2H, d, J6.9 Hz), 7.48 (1H, s), 7.13 (3H, brs), 6.83 (1H, s), 4.18 (2H, m), 3.90(3H, s), and 3.30 (2H, m).

EXAMPLE 55-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxgyhenyl)pyrimidine-2-amine

[0161] To a solution of the compound of Example 3 (210 mg, 0.5 mmol) indry THF (20 ml) at 0°, under a nitrogen atmosphere, was added DIBAL-H(1M in THF) (2.5 ml, 2.5 mmol) and the reaction was allowed to warm toambient temperature over 4.5 h. The reaction was quenched with 1Mpotassium-sodium tartrate (75 ml) and extracted with ethyl acetate (2×75ml). The organic phase was dried (MgSO₄), concentrated under reducedpressure and the residue subjected to column chromatography (silica gel;3% methanol-dichloromethane) to give the title compound (150 mg) as ayellow solid m.p.188-191°. δH (d⁶DMSO) 10.46 (1H, br s), 8.92 (1H, s),7.99 (2H, br m), 7.54(2H, d, J 8.0 Hz), 7.23 (2H, br s), 5.37 (2H, t, J4.1 Hz), 4.58 (2H, d, J 4.1 Hz), 3.73 (6H, s) and 3.53 (3H, s).

EXAMPLE 65-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0162] The compound of Example 5 was dissolved in chloroform (10 mL),thionyl chloride (37 μl) added and the resulting solution heated atreflux for 0.1 h. The reaction was concentrated under reduced pressureand the residue taken up in acetonitrile (6 ml) to whichN,N-diethylamine (150 μl) was added. After heating at reflux for 5 h themixture was concentrated under reduced pressure and the residue wassubjected to column chromatography (silica gel; 5%methanol-dichloromethane) to give the title compound as a yellow solidm.p. 137°. δH (d⁶ DMSO) 8.68 (1H, s), 8.05 (2H, d, J 8.0 Hz), 7.55-7.51(3H, m), 7.00 (2H, br s), 3.88 (6H,s), 3.85 (3H, s), 2.56 (4H, q, J 7.1Hz) and 1.07 (6H, t, J 7.1 Hz).

EXAMPLE 75-Cyano-4-[2-(3-(R)-dimethylaminopyrrolidin-1-yl)pyrldin-5-yl]-N-(indazol-5-yl)pyrimidine-2-amine

[0163] 4-(2-Chloropyddin-5-yl)-5-cyano-N-(indazol-5-yl)pydmidine-2-amine(522 mg, 1.5 mmol) and 3-(R)-dimethylaminopyrrolidine were heatedtogether at 140° in a sealed flask for 2 h. On cooling the reactionmixture was triturated with water to give a brown solid which wascollected and subjected to column chromatography (silica gel; 1%triethylamine-10% methanol-89% dichloromethane) to give the titlecompound (417 mg) as a yellow solid m.p.249-250°. δH (d⁶ DMSO) 13.00(1H, br s), 10.32 (1H, s), 8.81 (2H, d, J 9.2 Hz), 8.15-8.12 (2H, m),8.04 (1H, s), 7.59 (1H, m), 7.52 (1H, d, J 9.8 Hz), 6.63 (1H, d, J 9.0Hz), 3.77-3.67 (2H, m), 3.41-3.24 (2H, m), 2.82 (1H, br m), 2.22 (6H,s), 2.21 (1H, m) and 1.84 (1H,m).

[0164] The chloropyridine used as starting material was prepared fromindazol-5-ylguanidinium nitrate (1.51 g,6.36 mmol),1-(2-chloropyridin-5-yl)-2-cyano-3-dimethylaminopropen-1-one (1.50 g,6.36 mmol) and sodium hydroxide (254 mg, 6.36 mmol) to give the desiredproduct (1.49 g) as a white solid m.p. >285 (decomp).

[0165] The propenone was prepared from3-(2-chloropyridin-5-yl)-3-oxopropio-nitrile (4.2 g, 23.3 mmol) anddimethylformamide diethylacetal (13 ml) to give the desired material(5.05 g) as an off-white solid m.p. 130-132°.

[0166] 3-(2-Chloropyridin-5-yl)-3-oxopropionitrile was prepared bytreating a solution of cyanoacetic acid (9.10 g, 53.5 mmol) and2,2′-bipyridyl (5 mg) in dry THF (500 ml), cooled to −70° under anitrogen atmosphere, dropwise with n-butyllithium (85.6 ml, 214 mmol ofa 2.5M solution in hexane). The reaction was allowed to warm to 0° overa period of 1 h and then recooled to −70°, at which point a solution of6-chloronicotinyl chloride (9.42 g, 53.5 mmol) in THF (75 ml) was addedto the resulting red slurry. The reaction was stirred at −70° for afurther 1 h upon complete addition, and then allowed to reach 0 whereupon 2M hydrochloric acid (250 ml) was added. The reaction was extractedwith chloroform (2×400 ml) and the combined organic phases were thenwashed with saturated aqueous NaHCO₃ (1×250 ml) and saturated brine(1×250 ml), dried (MgSO₄) and concentrated under reduced pressure. Theresulting solid was triturated with diethyl ether/n-hexane (1:5) to givethe desired material (4.20 g) as a pale yellow powder m.p. 122-123°.

[0167] Indazol-5-ylguanidinium nitrate was prepared from 5-aminoindazole(4.0 g,mmol), cyanamide (1.89 g, 45.1 mmol) and concentrated HNO₃ (2.8ml) to give the desired material as a solid m.p. 252-254°.

EXAMPLE 84-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-indazol-5-yl)pyrimidine-2-amine

[0168] A mixture of indazol-5-ylguanidinium nitrate (524 mg, 2.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropen-1-one(714 mg, 2.0 mmol) and powdered sodium hydroxide (96 mg, 2.4 mmol) inpropan-2-ol (30 ml) was heated at reflux for 6 h. The reaction wasconcentrated in vacuo and the residue purified by column chromatography(silica, 60% ethyl acetate in hexane, loading the crude material indichloromethane) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2-amineas a yellow solid (850 mg). δH (CDCl₃) 8.69 (1H, s), 8.18 (1H, s), 8.11(I H, s), 8.05 (2H, d, J 8.4 Hz), 7.93 (1H, bs), 7.57 (2H, d, J 8.4 Hz),7.50 (2H, m), 5.10 (1H, bs), 1.66 (6H, s), 1.40 (9H, bs). MS (ESI) 492(MNa+, 61%), 470 (MH+, 100%), 414 (19%). This product was dissolved in amixture of TFA acid (20 ml) and CH₂Cl₂ (20 ml) and was stirred for 30mins at room temperature before concentrating the reaction in vacuo. Theresidue was dissolved in 10% MeOH in CH₂Cl₂ (200 ml) and the organicphase washed with sat. Na₂CO₃ (aq) (50 ml), dried (MgSO₄) andconcentrated in vacuo to give the title compound as a bright yellowsolid (541 mg) m.p. 267-271° (dec.). δH (d⁶ DMSO) 13.03 (1H, bs), 10.46(1H, s), 8.91 (1H, s), 8.16 (1H, s), 8.04 (1H, s), 7.94 (2H, d, J 8.4Hz), 7.74 (2H, d, J 8.4 Hz), 7.61 (1H, m), 7.52 (1H, d, J 8.9 Hz), 3.44(2H, bs), 1.48 (6H, s). MS (ESI) 392 (MNa+, 11%), 370 (MH+, 23%),353(100%).

[0169] The1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-aminopropen-1-oneused in the above process was prepared as follows:

[0170] A mixture of 4-acetylbenzonitrile (51.84 g, 0.357 mol) andN,N-dimethylformamide dimethyl acetal (142 ml, 1.07 mol) was heated toreflux for 1.5 h. The reaction was cooled to room temperature and theresultant crystalline mass collected by filtration and washed withdiethyl ether (4×100 ml) to give1-(4-cyanophenyl)3-dimethylaminopropen-1-one as an orange solid (44.56g). An additional crop of this product (11.40 g) could be obtained bypartially concentrating the filtrate. δH (d⁶ DMSO) 8.01 (2H, d, J 8.2Hz), 7.87 (2H, d, J 8.2 Hz), 7.75 (1H, d, J 12.2 Hz), 5.83 (1H, d, J12.2 Hz), 3.15 (3H, bs), 2.92 (3H, bs). MS (ESI) 201 (MH+, 100%).

[0171] Hydroxylamine hydrochloride (21.40 g, 308 mmol) was added to asuspension of 1-(4-cyanophenyl)3-dimethylaminopropen-1-one (55.96 g, 280mmol) in MeOH (450 ml) and the reaction stirred at room temperature for24 h. The reaction was diluted with water (400 ml) and the resultantprecipitate collected by filtration, washed with water (5×150 ml) anddried in vacuo to give 4-(5-isoxazolyl)-benzonitrile as a pale yellowsolid (42.53 g) m.p. 148-149°. δH (CDCl₃) 8.35 (1H, d, J 1.8 Hz), 7.91(2H, d, J 8.3 Hz), 7.77, (2H, d, J 8.3 Hz), 6.66 (1H, d, J 1.8 Hz).

[0172] Cerium trichloride heptahydrate (112.6 g, 302 mmol) was driedunder vacuum (0.6 mbar) at 140-150 (oil bath) for 4 h in a flask fittedwith a large magnetic stirring bar. The flask was refilled withnitrogen, cooled to 0° with an ice bath and anhydrous THF (500 ml)introduced with stirring. On complete addition the ice bath was removedand the milky suspension stirred at room temperature for 16 h. Thereaction was cooled to −78° and methyl lithium (188 ml of a 1.6Msolution in diethyl ether, 300 mmol) added dropwise with stirring. After45 mins a solution of 4-(5-isoxazolyl)-benzonitrile (17.0 g, 100 mmol)in anhydrous THF (100 ml) was added and the reaction mixture left towarm in the cooling bath from −78° to −10° over 3 h. The reaction wasquenched with 33% ammonium hydroxide (250 ml) and filtered through a padof Celite® to remove the resultant solids. The Celite® pad was washedthoroughly with ethyl acetate (4×100 ml) and the combined filtratesconcentrated to approximately 200 ml. These filtrates were diluted withbrine (200 ml) and extracted with ethyl acetate (2×150 ml), the organicextracts were dried (MgSO₄) and concentrated in vacuo to give1-[4-(5-isoxazolyl)phenyl]-1-methylethylamine as a yellow solid (19.53g). δH (CDCl₃) 8.27 (1H, d, J 1.9 Hz), 7.76 (2H, dt, J 8.7, 2.0 Hz),7.62 (2H, d, dt, J 8.7, 2.0 Hz), 6.49 (1H, d, J 1.9 Hz), 1.94 (2H, bs),1.53 (6H, s). This compound was used in the following step withoutpurification. A mixture of 1-[4-(5-isoxazolyl)phenyl]-1-methylethylamine(23.87 g, 11 8.2 mmol) and di-tert-butyl dicarbonate (28.37 g, 130 mmol)in toluene (200 ml) was heated to reflux for 1 h before removing solventin vacuo. The resultant solid was recrystallised from ethanol to givetert-butyl N-{1-[4-(5-isoxazolyl)phenyl]-1-methylethyl} carbamate asbrightyellowcrystals (24.90 g) m.p.145-146°. δH (CDCl₃) 8.27 (1H, d, J1.8 Hz), 7.75 (2H, d t, J 8.7, 2.1 Hz), 7.50 (2H, d t, J 8.7, 2.1 Hz),6.49 (1H, d, J 1.8 Hz), 4.97 (1H, bs), 1.64 (6H, s), 1.37 (9H, bs). MS(ESI) 325 (MNa+,42%), 303 (MH+,56%),186 (100%).

[0173] A freshly prepared solution of sodium ethoxide (3.77 g, 164 mmolof sodium in 150 ml of ethanol) was added to a suspension of tert-butylN-{1-[4-(5-isoxazolyl)phenyl]-1-methylethyl}carbamate (24.76 g, 82 mmol)in ethanol (150 ml) and the reaction stirred at room temperature for 1h. Ethanol was removed in vacuo and the residue partitioned betweenethyl acetate (150 ml) and cold 1M hydrochloric acid (250 ml). Theaqueous layer was re-extracted with ethyl acetate (2×80 ml) and thecombined ethyl acetate extracts washed with brine (100 ml), dried(MgSO₄) and concentrated in vacuo to give tert-butylN-{1-[4-(2-cyanoacetyl)phenyl]-1-methylethyl} carbamate as an off-whitesolid m.p.122-123°. This crude product was dissolved in THF (150 ml),N,N-dimethylformamide diethyl acetal (14.48 g, 98.4 mmol) added and themixture heated to 50 for 1 h. Solvent was removed in vacuo and theresidue purified by column chromatography (silica, 2-4% MeOH in CH₂Cl₂)to give1-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropen-1-oneas a pale yellow solid (24.46 g) m.p. 160-162°. δH (CDCl₃) 7.94 (1H, s),7.77 (2H, dt, J 8.6, 1.9 Hz), 7.45 (2H, dt, J 8.6, 1.9 Hz), 5.08 (1H,bs), 3.48 (3H, s), 3.28 (3H, s), 1.63 (6H, s), 1.32 (9H, bs). MS (ESI)380 (MNa+, 63%), 358 (MH+, 32%), 302 (96%), 241 (100%).

EXAMPLE 94-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0174] The title compound was prepared from3,4,5-trimethoxyphenylguanidinium nitrate (576 mg, 2.0 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropen-1-one (660 mg, 1.8 mmol) andpowdered sodium hydroxide (89 mg, 2.2 mmol) following the methoddescribed for the compound of Example 8. This gave the intermediate4-[4-(1-tert-butoxycabonylamino-1methylethyl)phenyl]-5-cyano-N-(3,4,5-tri-methoxyphenyl)pyrimidine-2-amineas a yellow solid (769 mg) after column chromatography (silica, 40%ethyl acetate in hexane). This compound was treated with TFA acid inCH₂Cl₂ as descibed for the analogous compound of Example 8 to give thetitle compound as a pale yellow solid (597 mg) m.p. 167-168°. δH (d⁶DMSO) 10.34 (1H, bs), 8.90 (1H, s), 7.96 (2H, bd, J 7.8 Hz), 7.73 (2H,d, J 8.2 Hz), 7.24 (2H, bs), 3.76 (6H, s), 3.63 (3H, s), 3.18 (2H, bs),1.42 (6H, s). MS (ESI) 442 (MNa+, 16%),420 (MH+, 57%), 403 (100%).

[0175] Except where otherwise indicated, the following compounds ofExamples 10-23 and their respective intermediates were prepared in amanner to the compound of Example 8 and its intermediates:

EXAMPLE 104-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[(4-imidazol-1-yl)phenyl]pyrimidine-2-amine

[0176] From 4-(imidazol-1-yl)phenylguanidinium nitrate (916 mg, 2.8mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone(1.0 g, 2.8 mmol) and powdered sodium hydroxide (224 mg, 3.6 mmol) togive4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N[(4-imidazol-1-yl)phenyl]pyrimidine-2-amineas a yellow solid (675 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (471 mg) m.p. 232-233°. δH (d⁶ DMSO) 10.51 (1H. bs), 8.95 (1H, s),8.19 (1H, s), 7.93-7.89 (4H, m), 7.76-7.61 (5H, m), 7.08 (1H, s), 2.20(2H, bs) and 1.41 (6H, s).

EXAMPLE 114-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(1,2.4-triazol-1-yl)phenyl]pyrimidine-2-amine

[0177] From 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate (750 mg, 2.8mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-aminopropenone (1.0 g, 2.8 mmol) and powdered sodium hydroxide (150 mg, 3.75mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amineas a yellow solid (380 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (224 mg) m.p. 208-209°. δH (d⁶ DMSO) 10.67 (1H, bs), 9.21 (1H, s),8.97 (1H, s), 8.20 (1H, s), 7.97-7.94 (4H, m), 7.82 (2H, d, J 9.1 Hz),7.76 (2H, d,J 8.9 Hz), 2.09 (2H, bs) and 1.41 (6H, s).

[0178] The guanidine used as starting material in the above process wasprepared from 4-(1,2,4-triazol-1yl)aniline (1.60 g, 10.0 mmol).cyanimide (715 mg, 17 mmol) and concentrated HNO₃ (725 mL, 11 mmol), ina manner similar to the corresponding starting material of Example 1, asa beige solid (1.50 g) m.p. >310° (decomp).

[0179] 4-(1,2,4-triazol-1yl)aniline was prepared by suspending4-(1,2,4-triazol-1-yl)nitobenzene (2.25 g,11.83 mmol) with 10% palladiumon charcoal in ethanol (125 ml), containing 4M hydrochloric acid (75mL). The resulting mixture was stirred under a hydrogen atmosphere atnormal pressure and room temperature for 16 h. The reaction was filteredthrough a pad of Celite® washing thoroughly with ethanol. The filtratewas concentrated to 50 mL in volume and 2M NaOH added until the pHwas >10. The solution was again concentrated to 50 mL and cooled to 0°.The resulting solid was collected by filtration and washed sparinglywith water to give the desired material (1.65 g) as an off-white solid,m.p. 150-152°.

[0180] The nitrobenzene used in the above process was prepared byheating a mixture of 4-fluornitrobenzene (40 g, 28.3 mmol) and1,2,4-triazole, sodium salt (28.4 g, 31.2 mmol) in DMF (250 mL) at 80ofor 4 h. On cooling the reaction was poured into cooled saturated brine(600 mL) and 2M NaOH (400 mL). The resulting solid was collected byfiltration, washed with 2M NaOH (2×150 mL), water (3×100 mL) thenethanol (2×75 mL) and dried under high vacuum. The product was purifiedby column chromatography (silica 3% MeOH in dichloromethane) to give thedesired material as a yellow solid (9.05 g).

EXAMPLE 124-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(1,2,3-triazol-1-yl)phenyl]pyrimidine-2-amine

[0181] From 4-(1,2,3-triazol-1-yl)phenylguanidinium nitrate (750 mg, 2.8mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.0 g, 2.8 mmol) and powdered sodium hydroxide (150 mg,3.75 mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amineas a yellow solid (380 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (224 mg) m.p. 208-209°. δH (d⁶ DMSO) 10.67 (1H, bs), 9.21 (1H, s),8.97 (1H, s), 8.20 (1H, s), 7.97-7.94 (4H, m), 7.82 (2H, d, J 9.1 Hz),7.76 (2H, d, J 8.9 Hz), 2.09 (2H, bs) and 1.41 (6H, s).

[0182] 4-(1,2,3-triazol-1-yl)phenylguanidinium nitrate was prepared from4-(1,2,3-triazol-1-yl)aniline (1.42 g, 8.87 mmol), cyanamide (635 mg,15.1 mmol) and concentrated HNO₃ (645 ml, 9.67 mmol) in a manner similarto the corresponding starting material of Example 1, as a white solid(1.0 g), m.p. >320°.

[0183] The aniline used in the above process was prepared byhydrogenation of 4-(1,2,3-triazol-1-yl)nitrobenzene (1.86 g, 9.78 mmol)in ethanol (75 mL) over 10% palladium on charcoal (500 mg) atatmospheric pressure and room temperature for 20 h. The catalyst wasremoved by filtration through Celite® and the filtrate concentrated togive the desired product as an off-white solid (1.43 g), m.p. 139-140°.

EXAMPLE 134-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,5-difluorophenyl)pyrimidine-2-amine

[0184] From 3,5-difluorophenylguanidinium nitrate (983 mg, 2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone(1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.3 mmol) togive4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3,5-difluorophenyl]pyrimidine-2-amineas a yellow solid (510 mg) after column chromatography (silica, 2% MeOHin dichloro-methane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (332 mg) m.p. 209°. δH (d⁶ DMSO) 9.06 (1H, s), 8.00 (2H, d, J 8.5Hz), 7.78 (2H, d, J 8.5 Hz), 7.62-7.54 (2H, m), 6.93-6.86 (1H, m) and1.60 (6H, s).

EXAMPLE 144-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluoro-4-methylphenyl)pyrimidine-2-amine

[0185] From 3-fluoro-4-methylphenylguanidinium nitrate (1.15 g, 5.0mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.78 g, 4.98 mmol) and powdered sodium hydroxide (176mg, 4.2 mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methyl-ethyl)phenyl]-5-cyano-N-[3-fluoro4-methylphenyl]pyrimidine-2-amineas a yellow solid (1.47 g) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (1.16) m.p. 209°. δH (d⁶ DMSO).8.96 (1H, s), 7.91 (2H,d, J 8.5Hz), 7.76 (2H,d, J 8.5 Hz), 7.70 (1H,m), 7.46-7.43 (1H, m), 7.27-7.21(1H, m) and 1.60 (6H, s).

EXAMPLE 154-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trifluorophenyl)pyrimidine-2-amine

[0186] From 3,4,5-trifluorophenylguanidinium nitrate (1.06 g, 4.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylamino-propenone(1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.2 mmol) togive4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3,4,5-trifluoro-phenyl]pyrimidine-2-amineas a yellow solid (597 mg) after column chromatography (silica, 2% MeOHin dichloro-methane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (401 mg) m.p. 220°. δH (d⁶ DMSO) 9.01(1H, s), 7.91 (2H, m),7.78-7.71 (4H, m) and 1.40 (6H, s).

EXAMPLE 164-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4-fluoro-3-trifluoromethylphenyl)pyrimidine-2-amine

[0187] From 4-fluoro-3-trifluoromethylphenylguanidinium nitrate (1.19 g,4.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylamino-propenone(1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.2 mmol) togive4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-fluoro-3-trifluoromethylphenyl]pyrimidine-2-amine as a yellow solid (648 mg) after column chromatography (silica,2% MeOH in dichloromethane). This compound (211 mg) was treated with TFAacid in CH₂Cl₂ as described for Example 8 to give the title compound asa pale yellow solid (157 mg) m.p. 181°. δH (d⁶ DMSO) 8.91 (1H, s), 8.32(1H, dd, J 6.5, 2.6 Hz), 8.06-8.00 (1H, s), 7.99 (2H, d, J 8.8 Hz), 7.77(2H, d, J 8.8 Hz), 7.44 (1H, m) and 1.47 (6H, s).

EXAMPLE 174-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(2,4-difluorophenyl)pyrimidine-2-amine

[0188] From 2,4-difluorophenylguanidinium nitrate (0.98 g, 4.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg,4.3mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[2,4,-difluoro-phenyl]pyrimidine-2-amineas a yellow solid (648 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (460 mg) m.p. 203°. δH (d⁶ DMSO) 8.65 (1H, s), 7.82 (2H, d, J 6.6Hz), 7.70 (2H, d, J 8.3 Hz), 7.61-7.55 (1H, m), 7.38-7.32 (1H, m),7.14-7.09 (1H, m) and 1.39 (6H, s).

EXAMPLE 184-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4-difluorophenyl)pyrimidine-2-amine

[0189] From 3,4-difluorophenylguanidinium nitrate (0.98 g, 4.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.3mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3,4-difluorophenyl]pyrimidine-2-amineas a yellow solid (631 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the tite compound as a pale yellowsolid (412 mg) m.p. 1920. δH (d⁶ DMSO) 10.66 (1H, bs), 8.97 (1H, s),7.99-7.92 (1H, m), 7.90 (2H, d, J 8.5 Hz), 7.76 (2H, d, J 8.5 Hz),7.53-7.38 (2H, m) and 1.41 (6H, s).

EXAMPLE 194-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-chloro-4-fluoro-phenyl)pyrimidine-2-amine

[0190] From 3-chloro-4-fluorophenylguanidinium nitrate (1.05 g, 4.2mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (1 76 mg,4.3 mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-chloro-4-fluorophenyl]pyrimidine-2-amineas a yellow solid (895 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (501 mg) m.p. 237°. δH (d⁶ DMSO) 10.60 (1H, bs), 8.97 (1H, s),8.07 (1H, d, J 6.8, 2.5 Hz), 7.91 (2H, dapp, J 8.5 Hz), 7.75 (2H, d, J8.5 Hz), 7.73-7.69 (1H, m), 7.41 (1H, tapp, J 9.1 Hz) and 1.41 (6H, s).

EXAMPLE 204-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine

[0191] From 4-fluorophenylguanidinium nitrate (0.91 g, 4.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.3mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-fluorophenyl]pyrimidine-2-amineas a yellow solid (1.28 g) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (607 mg) m.p. 228-229°. δH (d⁶ DMSO) 10.59 (1H, s), 9.02 (1H, s),8.00 (2H, d, J 8.4 Hz), 7.86-7.83 (4H, m), 7.32-7.27 (2H, m) and 1.51(6H, s).

EXAMPLE 214-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-trifluoromethylphenyl)pyrimidine-2-amine

[0192] From 3-trifluoromethylphenylguanidinium nitrate (1.12 g, 4.2mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.3mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-trifluoromethyl]pyrimidine-2-amineas a yellow solid (1.32 g) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA in CH₂Cl₂ asdescribed for Example 8 to give the title compound as a pale yellowsolid (607 mg) m.p. 192°. δH (d⁶ DMSO) 10.70 (1H, bs), 8.93 (1H, s),7.92 (1H, d, 18.3 Hz), 7.87 (2H, d, J 8.3 Hz), 7.68 (2H, d, J 8.3 Hz),7.51 (1H, t, J 8.0 Hz), 7.33 (1H, d, J 7.7 Hz) and 1.34 (6H, s).

EXAMPLE 224-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrimidine-2-amine

[0193] From 3-fluorophenylguanidinium nitrate (0.91 g, 4.2 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176 mg, 4.3mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-fluorophenyl]pyrimidine-2-amineas a yellow solid (381 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (161 mg) m.p. 209°. δH (d⁶ DMSO) 10.66 (1H, s), 8.98 (1H, s), 7.92(2H, dapp, J 8.5 Hz), 7.76 (2H, dapp, J 8.5 Hz), 7.74 (1H, m), 7.56-7.54(1H, m), 7.40-7.34 (1H, m), 6.91-6.86 (1H, m), 2.48 (2H, bs) and 1.41(6H, s).

EXAMPLE 234-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(phenyl)pyrimidine-2-amine

[0194] From phenylguanidinium nitrate (0.45 g, 2.8 mmol),1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (1.0 g, 2.8 mmol) and powdered sodium hydroxide (112 mg, 2.8mmol) to give4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[phenyl]pyrimidine-2-amineas a yellow solid (820 mg) after column chromatography (silica, 2% MeOHin dichloromethane). This compound was treated with TFA acid in CH₂Cl₂as described for Example 8 to give the title compound as a pale yellowsolid (589 mg) m.p. 303-304°. δH (d⁶ DMSO) 8.72 (1H. s), 8.09 (2H, d, J8.0 Hz), 7.69-7.58 (5H, m), 7.43-7.38 (2H, m), 7.15 (1H, t, J 7.7 Hz),2.32 (2H, bs) and 1.68 (6H, s).

EXAMPLE 244-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]phenyl}pyrimidine-2-amine

[0195]4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-piperidin-1-ylethyl)phenyl]pyrimidine-2-amine(380 mg) was stirred in 50% v/v CH₂Cl₂-TFA (5 mL) at room temperaturefor 30 min. The solvent was removed under reduced pressure and theresulting residue was redissolved in CH₂Cl₂, washed with saturatedaqueous NaHCO₃, dried (MgSO₄) and evaporated to give the title compound(240 mg) as a yellow solid, m.p.150°. δH (CDCl₃) 8.70 (1H, s), 8.01 (2H,d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.22 (2H,d, J 8.0 Hz), 2.84 (2H, m), 2.63 (2H, m), 2.52 (4H, m) and 1.51 (6H, s).

[0196] The pyrimidine used in the above process was prepared by stirring4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-p-toluene-sulphonyloxyethyl)phenyl]pyrimidine-2-amine(500 mg, 0.8 mmol) with piperidine (400 ml, 4 mmol) in DMF (5 mL) at 70°for 4 h. The solvent was then removed under reduced pressure and theresulting residue was redissolved in CH₂Cl₂, washed with saturatedaqueous NaHCO₃, saturated brine, dried (MgSO₄) and concentrated underreduced pressure. The resulting residue was subjected to columnchromatography (silica 7% MeOH in dichloromethane) to give the desiredmaterial (392 mg) as a yellow solid, m.p. 142°. δH (CDCl₃) 8.67 (1H, s),8.05 (2H, d, J 8.3 Hz), 7.58-7.55 (4H, m), 7.22 (2H, d, J 8.5 Hz), 5.00(1H, s), 2.88-2.82 (2H, m), 2.63-2.52 (6H, m), 1.66 (12H, bs) and1.48-1.39 (9H, m).

[0197] The tosylate used in the above process was prepared by stirring4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine(4.02 g, 8.5 mmol), 4-toluene-sulphonyl chloride (2.43 g, 12.7 mmol) and4-dimethylaminopyridine (150 mg) in dichloromethane (70 ml) at ambienttemperature for 12 h. The reaction was diluted with dichloromethane (70mL) and washed with 2M hydrochloric acid (150 mL). The organic phase wasseparated and washed with 2M hydrochloric acid, brine and water, dried(MgSO₄) and concentrated under reduced pressure. The resulting residuewas subjected to column chromatography (silica 40% ethyl acetate-hexane)to give the desired material (3.6 g) as a yellow solid 134°. δH (CDCl₃)8.68 (1H. s), 8.05 (2H, m), 7.72 (2H, d, J 8.4 Hz), 7.57 (4H, t, J 8.5Hz), 7.29 (2H, d, J 8.0 Hz), 7.15 (2H, d, J 8.5 Hz), 5.00 (1H, s), 4.22(2H, t, J 7.1 Hz), 2.96 (2H, t, J 7.1 Hz), 2.42 (3H, s), 1.67 (6H, bs)and 1.56 (9H).

[0198] The pyrimidine used in the above process was prepared from4-(2-hydroxyethyl)phenylguanidinium nitrate (3.73 g, 15.4 mmol),1-[4-(1-tert-butoxy-carbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropenone (5.0 g, 14.0 mmol) and powdered sodium hydroxide (672 mg 16.8mmol) to give the desired product (7.7 g) as a pale yellow solid, m.p.114°.

[0199] The following compounds of Examples 25-41 and their respectiveintermediates were prepared in an analogous mannerto those in Example 24except where othewise indicated:

EXAMPLE 254-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine

[0200] From4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine(370 mg,0.71 mmol) to give the title compound (290 mg) as a pale yellowsolid m.p. 184°. δH (d⁶ DMSO) 10.51 (1H, s), 8.90 (1H, s), 8.02 (2H, d,J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.62 (2H, d, J 8.0 Hz), 7.41 (1H, s),7.13 (3H, m), 6.81 (1H, s), 4.22 (2H, t, J 7.0 Hz), 3.0 (2H, t, J 7.0Hz) and 1.6 (6H, s).

[0201]4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-aminewas prepared from 4-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-p-toluenesulphonyloxyethyl)phenylpyrimidine-2-amine(500 mg,0.8 mmol) and imidazole (272 mg, 4.0 mmol) as a yellow solid(380 mg), m.p. 124°. δH (CDCl₃) 8.68 (1H, s), 8.04 (2H, m), 7.66-7.56(4H, m), 7.32 (1H, s), 7.04 (3H, m), 6.85 (1H, t, J 1.3 Hz), 5.03 (1H,s), 4.18 (2H, t, J 7.0 Hz), 3.05 (2H, t, J 7.0 Hz), 1.66 (6H, bs) and1.39 (9H, bs).

EXAMPLE 264-[4-(1-Anino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine

[0202] From4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)pheny]-5-cyano-N-[4-2-morpholinoethyl)phenyl]pyrimidine-2-amine(430 mg) to give the title compound (392 mg) as a pale yellow solid m.p.156°. δH (d⁶ DMSO) 10.40 (1H, s), 8.91 (1H, s), 7.93 (2H, d, J 8.4 Hz),7.74 (2H, d, J 8.4 Hz), 7.64 (2H, d, J 7.8 Hz), 7.19 (2H, d, J 8.5 Hz),3.56 (4H, m), 3.36 (8H, bm), 2.70 (2H, t, J 7.5 Hz), 2.51-2.46 (2H, m)and 1.49 (6H, s).

[0203]4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-aminewas prepared from 4-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-ptoluene-sulphonyloxyethyl)phenyl]pynmidine-2-amine(500 mg, 0.80 mmol) and morpholine (350μL, 4.0 mmol) as a yellow solid(440 mg), m.p. 200°. δH (CDCl₃) 8.66 (1H, s), 8.05 (2H, d, J 8.3 Hz),7.69 (1H, s), 7.58-7.55 (4H, m), 7.21 (2H, d, J 8.5 Hz), 5.04 (1H, s),3.74 (4H, t, J4.7 Hz), 2.83-2.78 (2H, m), 2.63-2.57 (2H, m), 2.53 (4H,t, J 4.7 Hz), 1.65 (6H, bs) and 1.38 (9H, bs).

EXAMPLE 274-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine

[0204] From4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amineto give the title compound (310 mg) as a yellow solid m.p. 138°. δH (d⁶DMSO) 10.51 (1H, s), 8.91 (1H, s), 8.00 (2H, d, J 8.0 Hz), 7.71 (2H, d,J 8.0 Hz), 7.62 (2H, d, J 8.0 Hz), 7.11 (2H, d, J 8.0 Hz), 7.03 (1H, s),6.71 (1H, s), 4.12 (2H, t, J 7.0 Hz), 3.33 (bs), 2.91 (2H, t, J 7.0 Hz),2.40 (2H, t, J 7.0 Hz), 1.62 (6H, s) and 1.11 (3H, t, J 7.0 Hz).

[0205]4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N{4-[2-(2-ethyl-imidazol-1-yl)ethyl]phenyl}pyrimidine-2-aminewas prepared from4-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-p[toluene-sulphonyloxyethyl)phenyl]pyrimidine-2-amine(500 mg, 0.80 mmol) and 2-ethylimidazole (383 mg) to give the titlecompound (400 mg) as a yellow solid, m.p. 210°. δH (CDCl₃) 8.68 (1H, s),8.05 (2H, d, J 8.4 Hz), 7.60-7.56 (5H, bm), 7.05 (2H, d, J 8.4 Hz), 6.94(1H, d, J 1.3 Hz), 6.76 (1H, d, J 1.3 Hz), 5.00 (1H, s), 4.07 (2H, t, J7.1 Hz), 3.00 (2H,t, J 7.1 Hz), 2.49 (2H, q, J 7.5 Hz), 1.67 (6H, bs),1.39-1.23 (9H,bm) and 0.88 (3H, t, J 7.0 Hz).

EXAMPLE 284-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4-(2-imidazol-1-ylethoxy)phenylpyrimidine-2-amine

[0206] From4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethoxy)phenyl]pyrimidine-2-amine(857 mg, 1.59 mmol) to give the title compound (566 mg) as a yellowsolid, m.p. 208-209°. δH (d⁶ DMSO) 10.32 (1H, bs), 8.86 (1H, s), 7.89(2H, d, J 8.5 Hz), 7.73 (2H, d, J 8.5 Hz), 7.67-7.63 (3H, m), 7.23 (1H,s), 6.94-6.88 (3H, m), 4.33 (2H, t, J 5.0 Hz), 4.22 (2H, t, J 5.1 Hz),2.01 (2H, bs) and 1.40 (6H, s).

[0207]4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-yl-ethoxy)phenyl]pyrimidine-2-aminewas prepared from4-[4-(1-tert-butoxycarbonylamino-1-methyl-ethyl)phenyl]-5-cyano-N-{4-[(2-p-toluene-sulphonyloxy)ethoxy]phenyl}pyrimidine-2-amine(2.0 g, 3.1 mmol) and imidazole (1.02 g, 15 mmol) as a yellow solid (870mg). δH (d⁶ DMSO) 10.34 (1H, s), 8.88 (1H, s), 7.90 (2H, d, J 8.5 Hz),7.68-7.64 (3H, m), 7.53 (2H, d, J 8.5 Hz), 7.31 (1H, bs), 7.24 (1H, t, J1.1 Hz), 6.93 (2H, d, J 19.0 Hz), 6.89 (1H, t, J 1.0 Hz), 4.35 (2H, t, J5.2 Hz), 4.23 (2H, t, J 5.2 Hz), 1.54 (6H, s) and 1.34 (9H, bs).

[0208]4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-{4-[(2-p-toluenesulphonyloxy)ethoxyl]phenyl}pyrimidine-2-aminewas prepared from4-[4-(1-tert-butoxy-carbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-hydroxyethoxy)phenyl]-pyrimidine-2-amine(2.1 g, 4.29 mmol) and 4-toluene sulphonylchloride (1.24 g, 6.5 mmol) asa yellow solid (2.10 g), m.p. 145-146°.

[0209]4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-hydroxyethoxy)phenyl]pyrimidine-2-aminewas prepared from 1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-3-dimethylamino-propenone (2.16 g,8.0 mmol), 4-(2-hydroxyethoxy)phenylguanidinium nitrate (2.08 g, 8.0mmol) and sodium hydroxide (320 mg, 8.0 mmol) as a pale green solid(2.28 g), m.p. 126-127°. δH (CDCl₃) 8.64 (1H, s), 8.06-8.02 (2H, m),7.58-7.51 (5H, m), 6.97-6.94 (2H, m), 5.03 (1H, bs), 4.14 (2H,t, J 5.2Hz), 4.00-3.95 (2H, bm), 2.12 (1H, bs), 1.68 (6H, s) and 1.38 (9H, bs).

[0210] The guanidine used in the above process was prepared by heating asolution of 4-(2-hydroxyethoxy)aniline (38.0 g, 0.25 mmol), cyanamide(17.67 g, 0.421 g) in 25 mL water, and concentrated HNO₃ (17.8 mL, 0.27mmol) in ethanol (350 mL) for 24 h. The reaction was cooled to 0° anddiluted with ether (350 mL). The resulting solid was collected byfiltration and dried to give the desired material as a purple solid(42.45 g). δH (d⁶ DMSO) 9.34 (1H, s), 7.18 (4H, bs), 7.16-7.12 (2H, m),7.01-6.96 (2H, m), 4.85 (1H, t, J 5.3 Hz), 3.98 (2H, t, J 5.2 Hz) and3.70 (2H, t, J 5.0 Hz).

EXAMPLE 294-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine

[0211] From4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine(400 mg, 0.73 mmol) to give the title compound (250 mg) as a pale yellowsolid m.p. 166-167°. δH (CDCl₃) 8.69 (1H, s), 8.05 (2H, d, J 8.5 Hz),7.68 (2H, d, J 8.7 Hz), 7.61 (1H, bs), 7.53-7.48 (2H, m), 7.30 (1H, t, J7.8 Hz), 7.00 (1H, d, J 7.5 Hz), 3.76-3.73 (4H, m), 2.87-2.81 (2H, m),2.67-2.61 (2H, m), 2.55-2.52 (4H, m), 1.83 (2H, bs) and 1.54 (6H, s).

[0212]4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-aminewas prepared from 4-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-p-toluene-suphonyloxyethyl)phenyl]pyrimidine-2-amine(500 mg, 0.84 mmol) and morpholine (293 μL, 3.36 mmol) as a yellow solid(413 mg). δH (CDCl₃) 8.68 (1H, s), 8.06 (2H, d, J 8.2 Hz), 7.58-7.51(5H, m), 7.30 (1H, t, J 7.8 Hz), 7.00 (1H, d, J 7.7 Hz), 5.04 (1H, bs),3.76-3.73 (4H, m), 2.86-2.81 (2H, m), 2.66-2.61 (2H, m), 2.55-2.52 (4H,m), 1.65 (6H, s) and 1.39 (9H, bs).

[0213]4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-p-toluenesuphonyloxyethyl)phenyl]pyrimidine-2-aminewas prepared from4-[4-(1-tert-butoxy-carbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-hydroxyethylphenyl]pyrimidine-2-amine (880 mg) and 4-toluenesulphonyl-chloride (572mg, 3.0 mmol) as yellow solid (945 mg). δH (CDCl₃) 8.68 (1H, s), 8.06(2H, d, J 7.9 Hz), 8.06 (2H, d, J 7.9 Hz), 7.60-7.53 (4H, m), 7.43 (1H,bs), 7.29-7.24 (3H, m), 6.90 (1H, d, J 7.0 Hz), 5.04 (1H, bs), 4.26 (2H,t, J 6.8 Hz), 2.98 (2H, t, J 7.0 Hz), 2.39 (3H, s), 1.66 (6H, s) and1.39 (9H, bs).

[0214]4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-hydroxyethyl)phenyl]pyrimidine-2-aminewas prepared from 4-[4-(1-tert-butoxycarbonylamino-1-methyl-ethyl)phenyl]-5-cyano-N-[3-(hydroxy-ethoxy)phenyl]pyrimidine-2-amine(2.0 g, 5.6 mmol), 3-(2-hydroxyethyl)-phenylguanidinium nitrate (1.6 g,5.6 mmol) and sodium hydroxide (336 mg, 8.4 mmol) as a yellow solid (980mg), m.p. 164-164°. δH (CDCl₃) 8.66 (1H, s), 8.05 (2H, d, J 8.4 Hz),7.71 (1H, bs), 7.59-7.51 (4H, m), 7.32 (1H, t, J 7.9 Hz), 7.01 (1H, d, J7.7 Hz), 5.06 (1H, bs), 3.89 (2H, t, J 6.5 Hz), 2.89 (2H, t, J 6.5 Hz),1.65 (6H, s) and 1.39 (9H, bs).

EXAMPLE 305-Cyano-4-phenyl-N-[4-(2-piperidin-1-ylethyl)phenyl]pyrimidine-2-amine

[0215] From5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine(800 mg, 1.70 mmol) and piperidine (0.84 mL,8.5 mmol) to give the titlecompound (367 mg) as a pale yellow solid, m.p. 124-125°. δH (CDCl₃) 8.69(1H, s), 8.05 (2H, d, J 6.8 Hz), 7.60-7.51 (6H, m), 7.22.(2H, d, J 8.4Hz), 2.87-2.83 (2H, m), 2.61-2.50 (6H, m), 1.66 (4H, bs) and 1.48-1.43(2H, m).

[0216]5-Cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidine-2-aminewas prepared from5-cyano-4-phenyl-N-[4-(2-hydroxyethyl)-phenyl]pyrimidine-2-amine (3.30g, 10.43 mmol) and 4-toluenesulphonylchloride (2.19 g, 11.47 mmol) as apale yellow solid (3.91 g) m.p. 134-135°. δH (d³ DMSO) 8.69 (1H, s),8.05 (2H, dd, J 6.0, 2.0 Hz), 7.72 (2H, d, J 8.3 Hz), 7.61-7.51 (6H, m),7.29 (2H, d, J 8.1 Hz), 7.14 (2H, d, J 8.5 Hz), 4.21(2H, t, J 7.0 Hz),2.95 (2H, t, J 7.0 Hz) and 2.41 (3H, s).

[0217] 5-Cyano-4-phenyl-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-aminewas prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (4.0 g,20 mmol), 4-(2-hydroxyethyl)phenyl-guanidinium nitrate (4.24 g,20 mmol)and sodium hydroxide (800 mg, 20.0 mmol) as a yellow solid (3.50 g),m.p. 142-143°. δH (CDCl₃) 8.68 (1H, s), 8.03 (2H, dd, J 6.0, 2.0 Hz),7.66 (1H, bs), 7.59-7.51 (5H, m), 7.23 (2H, m), 3.88 (2H, t, J 6.5 Hz),2.87 (2H, t, J 6.5 Hz) and 1.62 (2H, bs).

EXAMPLE 315-Cyano-4-phenyl-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine

[0218] From5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]-pyrimidine-2-amine(800 mg, 1.70 mmol) and imidazole (578 mg, 8.50 mmol) to give the titlecompound (378 mg) as a yellow solid m.p. 210-211°. δH (CDCl₃/d⁶ DMSO)10.28 (1H, bs), 8.74 (1H, s), 7.99 (1H, s), 7.94 (1H, d, J 6.7 Hz), 7.65(2H, d, J 8.74 Hz), 7.57-7.49 (2H, d, J 6.7 Hz), 7.03 (2H, d, J 8.4 Hz),6.98 (1H, s), 6.85 (1H, t, J 0.9 Hz), 4.16 (2H, t, J 7.1 Hz) and 2.97(2H, t, J 7.1 Hz).

EXAMPLE 325-Cyano-4-phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}-pyrimidine-2-amine

[0219] From5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]-pyrimidine-2-amine(800 mg, 1.70 mmol) and 2-ethylimidazole (817 mg, 8.5 mmol) to give thetitle compound (480 mg) as a yellow solid, m.p. 190-192°. δH (CDCl₃)8.72 (1H, s), 8.07 (2H, dd, J 5.4, 1.4 Hz), 7.75 (1H, bs), 7.62-7.54(5H, m), 7.06 (2H, d, J 8.5 Hz), 6.98 (1H, d, J 1.3 Hz), 6.79 (1H, d, J1.3 Hz), 4.09 (2H, t, J 7.0 Hz), 3.02 (2H, t, J 7.0 Hz), 2.51 (2H, q, J7.6 Hz) and 1.27 (3H, t, J 7.6 Hz).

EXAMPLE 335-Cyano-4-phenyl-N-{4-[2-(1,2,4-triazol-1-ylethyl)phenyl}pyrimidine-2-amine

[0220] From5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]-pyrimidine-2-amine(500 mg,1.12 mmol) and 1,2,4-triazole, sodium salt (122 mg, 1.35 mmol)to give the title compound (188 mg) as a yellow solid, m.p. 217-218°. δH(d⁶ DMSO) 10.48 (1H, s), 8.94 (1H, s), 8.33 (1H, s), 7.96 (3H, m),7.68-7.59 (5H, m), 7.11 (2H, d, J 8.5 Hz), 4.42 (2H, t, J 7.1 Hz) and3.08 (2H, t, J 7.1 Hz).

EXAMPLE 345-Cyano-4-phenyl-N-[4-(2-imidazol-1-ylethoxy)phenyl]pyrimidine-2-amine

[0221] From5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-pyrimidine-2-amine(1.54 g,3.17 mmol) and imidazole (1.08 g, 15.8 mmol) to give the titlecompound (790 mg) as a yellow solid, m.p.185°. δH (CDCl₃) 8.67 (1H, s),8.04 (2H, d, J 8.1 Hz), 7.60 (1H, s), 7.58-7.52 (5H, m), 7.45 (1H, s),7.07 (1H, s), 7.05 (1H, t, J 1.2 Hz), 6.91 (1H, d, J 2.2 Hz), 6.88 (1H,d, J 2.2 Hz), 4.35 (2H, t, J 5.0 Hz) and 4.23 (2H, t, J 5.0 Hz).

[0222]5-cyano4phenyl-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]pyrimidine-2-aminewas prepared from5-cyano-4-phenyl-N-[4-(2-hydroxy-ethoxy)phenyl]-pyrimidine-2-amine (1.42g,4.28 mmol) and 4-toluene-sulphonyl chloride (1.23 g, 6.4 mmol) as ayellow solid, m.p. 147°. δH (CDCl₃) 8.67 (1H, s), 8.05-8.03 (2H, m),7.83 (2H, dd, J 6.5, 1.8 Hz), 7.58-7.49 (6H, m), 7.35 (2H, dd, J 8.6,0.9 Hz), 6.83 (2H, d, J 0.9 Hz), 4.38-4.36 (2H, m), 4.18-4.16 (2H, m)and 2.45 (3H, s).

[0223]5-cyano-4-phenyl-N-[4-(2-hydroxyethoxy)phenyl]pyrimidine-2-aminewas prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.41 g,7.0 mmol), 4-(2-hydroxy-ethoxy)phenylguanidinium nitrate (2.0 g, 7.7mmol) and sodium hydroxide (340 mg, 8.4 mmol) to give a yellow solid(1.54 g), m.p. 151°. δH (CDCl) 8.67 (1H. s), 8.04 (2H, d, J 7.7 Hz),7.58-7.52 (5H, m), 7.45 (1H, s), 6.95 (2H, dd, J 6.7,2.3 Hz), 4.12-4.09(2H, m), 4.00-3.97 (2H, m) and 2.05-2.01 (1H, m).

EXAMPLE 355-Cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethoxy]phenyl}-4-thien-2-ylpyrimidine-2-amine

[0224] From5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyrimidine-2-amine(1.5 g, 3.0 mmol) and 2-ethylimidazole (1.46 g, 15.2 mmol) to give thetitle compound (0.94 g) as a pale yellow solid, m.p. 205°. δH (CDCl₃)8.59 (1H, s), 8.41 (1H, d, J 4.0 Hz), 7.63 (1H, d, J 5.0 Hz), 7.53 (2H,m), 7.37 (1H, s), 7.22 (1H, m), 6.97 (2H, d, J 6.5 Hz), 6.88 (2H, d, J9.0 Hz), 4.24 (4H, dd, J 6.8, 4.3 Hz), 2.78 (2H, q, J 7.8 Hz) and 1.39(3H, t, J 7.5 Hz).

[0225]5-cyano-N-(4-(2-p-toluenesulphonyloxyethoxy)phenyl]4thien-2-ylpydmidin-2-aminewas prepared from5-cyano-N-[4-(2-hydroxyethoxy)-phenyl]4-thien-2-ylpyrimidine-2-amine(8.02 g, 23.7 mmol) and 4-toluene-sulphonylchloride (9.0 g, 47.4 mmol)to give a yellow solid (4.97 g), m.p. 160°. δH (d⁶ DMSO) 10.32 (1H, s),8.84 (1H, s), 8.26 (1H, d, J 3.9 Hz), 7.99 (1H, d, J 5.0 Hz), 7.80 (2H,d, J 8.3 Hz), 7.64 (2H, m), 7.47 (2H, d, J 8.3 Hz), 7.33 (1H, t, J 4.5Hz), 6.85 (2H, d, J 9.0 Hz), 4.33 (2H, t, J 4.0 Hz), 4.15 (2H, m) and2.41 (3H, s).

EXAMPLE 365-Cyano-N-[4-{2-(2-methylimidazol-1-ylethoxy}phenyl]-4-thien-2-ylpyrimidine-2-amine

[0226] From5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyrimidin-2-amine(2.0 g, 4.07 mmol) and 2-methylimidazole (1.67 g, 5 mmol) to give thetitle compound (0.87 g) as a yellow solid, m.p. 190°. δH (d6 DMSO) 10.30(1H, bs), 8.83 (1H, s), 8.25 (1H, d, J 3.8 Hz), 7.97 (1H, d, J 5.0 Hz),7.65 (1H, bs), 7.32 (1H. t, J 4.0 Hz), 7.10 (1H, s), 6.93 (2H, d, J 8.7Hz), 6.72 (1H, s), 4.23 (4H, m) and 2.32 (3H, s).

EXAMPLE 375-Cyano-N-[4-(2-imidazol-1-ylethoxy)phenyl]-4-thien-2-ylpyrimidine-2-amine

[0227] From5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyrimidin-2-amine(2.45 g,5.0 mmol) and imidazole (1.7 g, 25 mmol) to give the titlecompound (1.0 g) as a yellow solid, m.p. 199-200°. δH (d⁶ DMSO) 9.90(1H, bm), 8.76 (1H, d, J 1.0 Hz), 8.26 (1H, m), 7.92 (1H, dd, J 5.0, 1.1Hz), 7.65 (3H, m), 7.31 (1H, dd, J 5.0, 3.8 Hz), 7.20 (1H, t, J 1.2 Hz),6.94 (3H, m), 4.36 (2H, m) and 4.30 (2H, m).

EXAMPLE 385-Cyano-N-[4-(2-(1,2,4-triazol-1-yl)ethoxy)phenyl]-4-thien-2-ylpyrimidine-2-amine

[0228] From5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)pheny[l-4-thien-2-ylpyrimidin-2-amine(1.29 g, 3.6 mmol) and 1,2,4-triazole sodium salt (990 mg, 10.9 mmol) togive the title compound (500 mg) as a yellow solid, m.p. 180-182°. δH(d⁶ DMSO) 8.84 (1H, s), 8.56 (1H, s), 8.24 (1H, d, J 4.Hz), 7.98-7.99(2H, m), 7.63 (2H, bs), 7.32 (1H, dd, J 4.0 Hz), 6.92 (2H, d, J 8.8 Hz),4.57 (2H, t, J 5.1 Hz) and 4.34 (2H, t, J 5.1 Hz).

EXAMPLE 395-Cyano-N-[4-(2-(1,3,4-triazol-1-yl)ethoxy)phenyl]-4-thien-2-ylpyrimidine-2-amine

[0229] From the same reactants in Example 38 and produced as as a sideproduct the title compound was obtained (100 mg) as a yellow solid, m.p.228°. δH (d⁶ DMSO) 8.84 (1H, s), 8.56 (2H, s), 8.25 (1H, d, J 3.9 Hz),7.98 (1H, d, J 4.9 Hz), 7.65 (2H, bs), 7.33 (1H, t, J 4.5 Hz), 6.95 (2H,d, J 8.9 Hz), 4.44 (2H, t, J 5.0 Hz) and 4.26 (2H, t, J 5.0 Hz).

EXAMPLE 405-Cyano-N-{4-[2-(1H-imidazol-2-ylamino)ethoxy]phenyl}-4-thien-2-ylpyrimidine-2-amine

[0230] From5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyrimidin-2-amine(500 mg, 0.78 mmol), and 2-aminoimidazole sulphate (500 mg, 3.78 mmol)and potassium carbonate (522 mg, 3.78 mmol) to give the title compound(170 mg) as a yellow solid, m.p. 140°. δH 8.84 (1H, s), 8.25 (1H, d, J4.0 Hz), 7.98 (1H, d, J 5.0 Hz), 7.76-7.60 (2H, m), 7.35-7.32 (1H, m),6.93 (2H, d, J 8.7 Hz), 6.64 (1H, s), 6.36 (1H, s), 5.34 (1H, m) and4.08 (4H, m).

EXAMPLE 415-Cyano-N-[4-(2-imidazol-1-ylethylphenyl]-4-thien-2-ylpyrimidine-2-amine

[0231] From5-cyano-[4-thien-2-yl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine(550 mg, 1.15 mmol) and imidazole (393 mg,5.77 mmol) to give the titlecompound (300 mg) as a yellow solid, m.p. 187°. δH (CDCl₃) 8.62 (1H,s),8.43(1H, dd, J 3.2, 1.0 Hz),7.65 (1H, dd, J 5.9, 0.0 Hz),7.59 (2H, d,J 8.2 Hz), 7.51 (1H, s), 7.35 (1H, s), 7.24 (1H, dd, J 4.0,1.0 Hz),7.10-7.05 (3H, m), 6.85 (1H, s), 4.19 (2H, t, J 7.0 Hz) and 3.06 (2H, t,J 7.0 Hz).

[0232] 5-Cyano-4-thien-2-yl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine was prepared from5-cyano-N-[4-(2-hydroxyethyl)phenyl]-4-thien-2-ylpyrimidine-2-amine(1.39 g, 4.30 mmol) and 4-toluenesulphonylchloride (1.23 g, 6.5 mmol) asa yellow solid (1.15 g), m.p. 190°. δH (CDCl₃) 8.62 (1H, s), 8.43 (1H,dd, J 3.1, 1.0 Hz), 7.66-7.61 (3H, m), 7.45 (1H, s), 7.28-7.22 (3H, m),3.73 (2H, t, J 7.3 Hz) and 3.09 (2H, t, J 7.3 Hz).

[0233]5-cyano-N-[4-(2-hydroxyethyl)phenyl]-4-thien-2-ylpyrimidine-2-amine wasprepared from 1-thien-2-yl-2-cyano-3-dimethylaminopropen-1one (2.17 g,10.5 mmol), 4-(2-hydroxy-ethyl)phenylguanidinium nitrate (2.8 g, 11.6mmol) and powdered sodium hydroxide (505 mg) as a yellow solid, m.p.178°. δH (d⁶ DMSO) 10.36 (1H, s), 8.86 (1H, s), 8.26 (1H, m), 8.00 (1H,d, J 4.1 Hz), 7.64 (2H, m), 7.33 (1H, dd, J 4.0, 1.0 Hz), 7.20 (2H, d, J8.4 Hz), 4.60 (1H, t, J 5.2 Hz), 3.58 (2H, t, J 7.0 Hz) and 2.69 (2H, t,J 7.0 Hz).

[0234] The compounds following Examples 42-71 were prepared in a similarmanner to the compound of Example 1:

EXAMPLE 425-Cyano-N-[4-(imidazol-1-yl)phenyl]-4-phenyl]pyrimidine-2-amine

[0235] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.5 g, 7.49mmol), 4-imidazol-1-ylphenylguanidinium nitrate (2.45 g,7.40 mmol) andsodium hydroxide (600 mg, 15 mmol) to give the title compound (1.40 g)as a yellow solid, m.p. 278-280°. δH 10.69 (1H, bs), 9.00 (1H, s), 8.21(1H, s), 7.98-7.91 (4H, m), 7.70-7.60 (6H, m) and 7.10 (1H, s).

EXAMPLE 435-Cyano-N-[4-(2-dimethylaminoethoxy)phenyl]-4-phenylpyrimidine-2-amine

[0236] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg,1.25mmol), 4-(2-dimethylaminoethoxy)phenylguanidinium nitrate (523 mg,1.25mmol) and sodium hydroxide (108 mg, 2.7 mmol) to give the title compound(230 mg) as a yellow solid, m.p. 152-153°. δH (d⁶ DMSO) 10.37 (1H, s),8.40 (1H, s), 7.94 (2H, m), 7.62 (5H, m), 6.94 (2H, dt, J 9.0, 2.0 Hz),4.02 (2H, t, J 5.8 Hz), 2.61 (2H, t, J 5.8 Hz) and 2.21 (6H, s).

EXAMPLE 445-Cyano-N-[3.5-dimethyl-4-(2-mordholinoethoxy)phenyl]-4-phenylpyrimidine-2-amine

[0237] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg, 1.25mmol), 3,5-dimethyl-4-(2-morpholinoethoxy)phenylguanidinium nitrate (523mg, 1.25 mmol) and sodium hydroxide (108 mg, 2.7 mmol) to give the titlecompound (317 mg) as a yellow solid, m.p. 160-162°. δH (d⁶ DMSO) 10.32(1H, s), 8.92 (1H, s), 7.96 (2H, m), 7.64-7.59 (3H, m), 7.42 (2H, bs),3.83 (2H, t, J 5.7 Hz), 3.59 (4H, t, J 4.6 Hz), 2.68 (2H, t, J 5.7 Hz),2.50 (4H, m) and 2.23 (6H, s).

EXAMPLE 45 5-Cyano-N-[3,5-dimethoxyphenyl]-4-phenylpyrimidine-2-amine

[0238] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg,1.25mmol), -3,5dimethoxyphenylguanidinium nitrate (321 mg, 1.4 mmol) andsodium hydroxide (56 mg, 1.4 mmol) to give the title compound (280 mg)as a yellow solid m.p. 206-207°. δH (d⁶ DMSO) 10.47 (1H, s), 8.98 (1H,s), 7.99 (2H, m), 7.63 (3H, m), 7.13 (2H, bs), 6.25 (1H, t, J 2.2 Hz)and 3.78 (3H, s).

EXAMPLE 46 5-Cyano-N-[3,4-dimethoxyphenyl]-4-phenylpyrimidine-2-amine

[0239] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg, 1.25mmol), 3,4-dimethoxyphenylguanidinium nitrate (348 mg, 1.25 mmol) andsodium hydroxide (56 mg) to give the title compound (107 mg) as anorange solid, m.p. 155-157°. δH (d⁶ DMSO) 9.78 (1H, bs), 8.80 (1H, s),8.00 (2H, m), 7.63-7.51 (3H, m), 7.25 (1H, dd, J 8.7, 2.5 mmol), 6.94(1H, d, J 8.7 mmol), 3.79 (3H, s) and 3.78 (3H, s).

EXAMPLE 47 5-Cyano-4-phenyl-N-[phenyl]pyrimidine-2-amine

[0240] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.0 g, 5.0mmol), phenylguanidinium nitrate (830 mg, 2.5 mmol) and sodium hydroxide(200 mg, 5.0 mmol) to give the title compound (660 mg) as a yellowsolid, m.p. 160-161°. δH (CDCl₃) 8.71 (1H, s), 8.08-8.05 (2H, m),7.66-7.51 (6H, m), 7.42-7.36 (2H, m) and 7.19-7.13 (1H, m).

EXAMPLE 485-Cyano-4-indol-3-yl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0241] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (1.0 g,4.18 mmol), 3,4,5-trimethoxyphenylguanidinium nitrate (1.20 g, 4.18mmol) and sodium hydroxide (167 mg, 4.18 mmol) to give the titlecompound (475 mg) as a yellow solid, m.p. 200-201°. δH (d⁶ DMSO) 12.04(1H, bs), 10.04 (1H, s), 8.77 (1H, s), 8.52 (1H, s), 8.50 (1H, bs), 7.52(1H, d, J 8.1 Hz), 7.24 (2H, t, J 7.4 Hz), 7.12 (2H, bs), 3.70 (6H, s)and 3.66 (3H, s).

[0242] 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one was preparedfrom 3-(cyanoacetyl)indole (4.0 g, mmol) and dimethylformamidedimethylacetal (4.1 mL, 23.9 mmol) as a yellow solid (2.4 g), m.p.187-188°. δH (d⁶ DMSO) 11.73 (1H, bs), 8.26 (1H, s), 8.12 (1H, dd, J6.8, 1.3 Hz), 7.98 (1H, s), 7.47-7.44 (1H, m), 7.20-7.09 (2H, m), 3.35(3H, s) and 3.26 (3H, s).

[0243] 3-(Cyanoacetyl)indole was prepared by suspending indole (11.71 g,0.10 mmol) and potassium cyanoacetate (24.6 g, 0.2 mmol) in acetonitrile(300 mL), and to this methanesulphonylchloride (7.7 mL, 0.1 mmol) wasadded. The resulting mixture was stirred at ambient temperature for 1 h,and then sodium carbonate (10 g in 50 mL water) was added. After 5 min,the organic phase was separated, dried (Na₂SO₄) and concentrated underreduced pressure. The residue was recrystallised from ethanol (100 mL)to give the desired material as an orange solid (4.31 g), m.p. 226-227°.δH (d⁶ DMSO) 12.20 (1H, bs), 8.38 (1H, d, J 2.8 Hz), 8.14-8.10 (1H, m),7.53-7.50 (1H, m), 7.25-7.21 (2H, m) and 4.49 (2H, s).

EXAMPLE 495-Cyano-4-indol-3-yl-N-[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine

[0244] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (289 mg,1.2 mmol), 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate (320 mg, 1.2mmol) and sodium hydroxide (48 mg, mmol) to give the title compound (270mg) as a yellow solid, m.p. 329-330°. δH (d⁶ DMSO) 12.00 (1H, bs),10.39(1H, bs), 9.26 (1H, s), 8.84 (1H, s), 8.55 (2H, bm), 8.28-8.21 (1H, m),7.96 (2H, d, J 8.8 Hz), 7.86 (2H, d, J 8.8 Hz), 7.56-7.52 (1H, m),7.28-7.15 (2H, m) and 3.30 (1H, bs).

EXAMPLE 505-Cyano-4-thiazol-2-yl-N-3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0245] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (300 mg,13.8 mmol), 3,4,5-trimethoxyphenylguanidinium nitrate (436 mg, 15.2mmol) and sodium hydroxide (61 mg, 15.2 mmol) to give the title compound(324 mg) as a yellow solid, m.p. 223°. δH (d⁶ DMSO) 10.52 (1H, bs), 9.03(1H, s), 8.28 (1H, d, J 3.0 Hz), 8.22 (1H, d, J 3.0 Hz), 7.23 (2H, s),3.88 (6H, s) and 3.72 (3H, s).

[0246] 2-Cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one was preparedfrom 2-cyanoacetyl thiazole (400 mg, 2.94 mmol) and dimethylformamidedimethylacetal (1.5 mL) as a yellow solid, m.p. 1260 δH (CDCl₃) 8.89(1H, s), 7.96 (1H, d, J 3.3 Hz), 7.60 (1H, d, J 3.1 Hz), 3.54 (3H, s)and 3.35 (3H, s).

[0247] 2-Cyanoacetylthiazole was prepared by heating a solution of2-ethoxycarbonyl-thiazole (1.08 g, 6.88 mmol), acetonitrile (360 mL,7.57 mmol) and sodium hydride [60% dispersion in oil] (303 mg, 7.57mmol) in benzene (20 mL) and DMF (2 mL) at 800 for 90 min. On coolingthe resulting precipitate was collected by filtration and dissolved inwater (60 mL). The solution was poured into cold 2M hydrochloric acid(100 mL) and the resulting precipitate collected by filtration to givethe desired product (200 mg) as a yellow solid, m.p. 109°. δH (CDCl₃)8.06 (1H, d, J 2.9 Hz), 7.82 (1H, d, J 2.9 Hz) and 4.32 (2H, s).

EXAMPLE 515-Cyano4-thiazol-2-yl-N-[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine

[0248] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (300 mg,1.38 mmol), 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate (425 mg,1.38 mmol) and sodium hydroxide (61 mg, 1.52 mmol) to give the titlecompound (381 mg) as a yellow solid, m.p. 331°. δH (d⁶ DMSO) 10.86 (1H,bs), 9.30 (1H, s), 9.10 (1H, s), 8.31-8.25 (3H, m), 8.01 (2H, dapp, J8.6 Hz) and 7.93 (2H, dapp, J 8.6 Hz).

EXAMPLE 525-Cyano-N-[3,4-dimethoxyphenyl]-4-thiazol-2-ylpyrimidine-2-amine

[0249] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (500 mg,2.3 mmol), 3,4-dimethoxyphenylguanidinium nitrate (585 mg, 2.3 mmol) andsodium hydroxide (100 mg, 2.3 mmol) to give the title compound (721 mg)as yellow solid, m.p. 258°. δH (d⁶ DMSO) 9.98 (1H, bs), 8.66 (1H, s),7.96 (1H, d, J 3.1 Hz), 7.87 (1H, d, J 3.1 Hz), 7.20 (1H, d, J 1.8 Hz),6.96-6.93 (1H, m) and 6.67 (1H, d, J 8.4 Hz) and 5.79 (2H, s).

EXAMPLE 535-Cyano-4-thiazol-2-yl-N-{4-[2-(1,2,4triazol-1-yl)ethoxy]phenyl}pyrimidine-2-amine

[0250] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (500 mg,2.3 mmol), 4-[2-(1,2,4-triazol-1-yl)ethoxy]phenylguanidinium nitrate(714 mg, 2.3 mmol) and sodium hydroxide (1 00 mg, 2.3 mmol) to give thetitle compound (812 mg) as a yellow solid, m.p. 224°. δH (d⁶ DMSO) 10.02(1H, s), 8.70 (1H, s), 8.33 (1H, s), 8.01 (1H, d, J 3.1 Hz), 7.91 (1H,d, J 3.1 Hz), 7.77 (1H, s), 7.47 (2H, d, J 8.8 Hz), 6.79-6.76 (2H, m),4.41 (2H, t, J 5.2 Hz) and 4.23 (2H, t, J 5.2 Hz).

EXAMPLE 545-Cyano-4-thiazol-2-yl-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-amine

[0251] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700 mg,3.2 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium nitrate(1.0 g, 3.2 mmol) and sodium hydroxide (136 mg, 3.2 mmol) to give thetitle compound (0.98 g) as a yellow solid, m.p. 203°. δH (d⁶ DMSO) 10.21(1H, bs), 8.90 (1H, s), 8.21 (1H, d, J 2.9 Hz), 8.14 (1H, s), 8.11 (1H,d, J 2.9 Hz), 7.73 (1H, s), 7.68-7.66 (2H, m), 6.99-6.95 (2H, m), 4.81(2H, t, J 5.1 Hz) and 4.47 (2H, t, J 5.1 Hz).

EXAMPLE 555-Cyano-4-thiazol-2-yl-N-{4-[2-(1,2,3-triazol-2-yl)ethoxy]phenyl}pyrimidine-2-amine

[0252] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700 mg,3.2 mmol), 4-[2-(1,2,3-triazol-2-yl)ethoxy]phenylguanidinium nitrate(1.0 g, 3.2 mmol) and sodium hydroxide (136 mg, 3.2 mmol) to give thetitle compound (1.1 g) as a yellow solid, m.p. 203°. δH (d⁶ DMSO) 10.19(1H, s), 8.87 (1H, s), 8.19 (1H, d, J 3.1 Hz), 8.09 (1H, d, J 3.1 Hz),7.76 (2H, s), 7.66-7.62 (2H, m), 6.95-6.91 (2H, m), 4.80-4.78 (2H, m)and 4.52 (2H, t, J 5.5 Hz).

EXAMPLE 565-Cyano-N-[4-(2-imidazol-1-ylethoxy)phenyl]-4-thiazol-2-ylpyrimidine-2-amine

[0253] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700 mg,3.2 mmol), 4-(2-imidazol-1-ylethoxy)phenylguanidinium nitrate (1.0 g,3.2 mmol) and sodium hydroxide (160 mg, 3.8 mmol) to give the titlecompound (981 mg) as a yellow solid, m.p. 221°. δH (d⁶ DMSO) 9.93 (1H,s), 8.83 (1H, s), 8.16 (1H, d, J 3.12 Hz), 8.03 (1H, d, J 3.1 Hz),7.67-7.62 (3H, m), 7.18 (1H, d, J 1.0 Hz), 6.99-6.91 (3H, m) and4.37-4.29 (4H, m).

EXAMPLE 57 5-Cyano-N-[4-fluorophenyl]-4-thiazol-2-ylpyrimidine-2-amine

[0254] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700 mg,3.2 mmol), 4-fluorophenylguanidinium nitrate (700 mg, 3.2 mmol) andsodium hydroxide (160 mg, 3.2 mmol) to give the title compound (891 mg)as a yellow solid, m.p. 263°. δH (d⁶ DMSO) 10.10 (1H, s), 8.88 (1H, s),8.17 (1H, d, J 3.1 Hz), 8.05 (1H, d, J 3.1 Hz), 7.78-7.75 (2H, m),7.20-7.15 (2H, m).

EXAMPLE 585-Cyano4-phenyl-N-{4-[2-(1,2,4-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-amine

[0255] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (470 mg, 2.35mmol), 4-[2-(1,2,4-triazol-1-yl)ethoxy]phenylguanidinium nitrate (800mg, 2.6 mmol) and sodium hydroxide (113 mg, 2.8 mmol) to give the titlecompound (390 mg) as a yellow solid m.p. 105°. δH (d⁶ DMSO) 10.36 (1H,s), 8.89 (1H, s), 7.97 (1H, s), 7.92 (2H, d, J 7.9 Hz), 7.61-7.58 (5H,m), 6.90 (2H, d, J 9.1 Hz), 4.56 (2H, t, J 5.0 Hz) and 4.32 (2H, t, J5.0 Hz).

EXAMPLE 595-Cyano-4-phenyl-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-amine

[0256] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (412 mg, 2.05mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium nitrate (700mg, 2.06 mmol) and sodium hydroxide (100 mg, 2.5 mmol) to give the titlecompound (300 mg) as a yellow solid m.p. 178°. δH 10.37 (1H, s), 8.90(1H, s), 7.92 (2H, d, J 7.9 Hz), 7.73 (1H, s), 7.61-7.58 (5H, m), 6.92(2H, d, J 9.1 Hz), 4.77 (2H, t, J 5.1 Hz) and 4.38 (2H, t, J 5.1 Hz).

EXAMPLE 605-Cyano-4-phenyl-N-{4-[2-(1,2,3-triazol-2-yl)ethoxy]phenyl}pyrimidine-2-amine

[0257] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (470 mg, 2.55mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium nitrate (800mg, 2.56 mmol) and sodium hydroxide (113 mg, 2.8 mmol) to give the titlecompound (430 mg) as a yellow solid m.p. 156°. δH (d⁶ DMSO) 10.30 (1H,s), 8.89 (1H, s), 7.92 (2H, d, J 7.9 Hz), 7.79 (2H, s), 7.61-7.58 (5H,m), 6.89 (2H, d, J 9.1 Hz), 4.78 (2H, t, J 5.1 Hz) and 4.46 (2H, t, J5.1 Hz).

EXAMPLE 61 5-Cyano-N-[4-hvdroxyphenyl]-4-phenyl]pyrimidine-2-amine

[0258] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.51 g, 7.55mmol), 4-hydroxyphenylguanidinium nitrate (1.78 g, 8.3 mmol) and sodiumhydroxide (362 mg, 9.06 mg) to give the title compound (1.23 g) as ayellow solid, m.p. 201°. δH (d⁶ DMSO) 10.23 (1H, s), 9.26 (1H, s), 8.85(1H, d, J 1.0 Hz), 7.92 (2H, dd, J 7.0, 1.0 Hz), 7.59 (3H, m), 7.48 (2H,d, J 8.0 Hz) and 6.73 (2H, d, J 8.0 Hz).

EXAMPLE 625-Cyano-N-[4-(2-hydroxyethoxy)phenyl]-4-pyridin-3-ylpyrimidine-2-amine

[0259] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (1.20 g,5.95 mmol), 4-(2-hydroxyethoxy)phenylguanidinium nitrate (1.54 g, 5.95mmol) and sodium hydroxide (262 mg, 6.34 mmol) to give the titlecompound (1.28 g) as a yellow solid, m.p. 209-210°. δH (d⁶ DMSO) 10.43(1H, bs), 9.07 (1H, d, J 1.9 Hz), 8.93 (1H, s), 8.77 (1H. dd, J 4.8, 1.6Hz), 8.31-8.28 (1H, m), 7.65-7.60 (3H, m), 6.92 (2H, d, J 9.0 Hz), 4.82(1H, t, J 5.6 Hz), 3.96 (2H, t, J 5.0 Hz) and 3.69 (2H, q, J 5.1 Hz).

EXAMPLE 63 5Cyano-4-pyridin-3-yl-N-[4-(1,2,4-triazol-I-yl)phenyl]pyrimidine-2-amine

[0260] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (516 mg,2.56 mmol), 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate (679 mg,2.56 mmol) and sodium hydroxide (113 mg, 2.82 mmol) to give the titlecompound (425 mg) as a yellow solid, m.p. 250-251°. δH 10.79 (1H, bs),9.20 (1H, s), 9.12 (1H, s), 9.04 (1H, s), 8.81 (1H, bm), 8.35-8.32 (1H,bm), 8.20 (1H, s), 7.93 (2H, d, J 8.6 Hz), 7.82 (2H, d, J 8.6 Hz) and7.65 (1H, bs).

EXAMPLE 645-Cyano-N-[4-morpholinophenyl]-4-pyridin-3-ylpyrimidine-2-amine

[0261] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (516 mg,2.56 mmol), 4-morpholinophenylguanidinium nitrate (725 mg, 2.56 mmol)and sodium hydroxide (113 mg, 2.82 mmol) to give the title compound (707mg) as an orange solid, m.p. 199-200°. δH (d⁶ DMSO) 10.39 (1H, bs), 9.07(1H, d, J 1.8 Hz), 8.91 (1H, s), 8.78 (1H, dd, J 4.9,1.6 Hz), 8.31-8.28(1H, m), 7.65-7.56 (3H, m), 6.93 (2H, d, J 9.1 Hz), 3.74-3.70 (4H, m)and 3.07-3.04 (4H, m).

EXAMPLE 65 5-Cyano-N-[4-fluoroohenyl]-4-indol-3-ylpyrimidine-2-amine

[0262] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (950 mg,3.97 mmol), 4-fluorophenylguanidinium nitrate (858 mg, 3.97 mmol) andsodium hydroxide (176 mg) to give the title compound (200 mg) as anoff-white solid, m.p. 256-257°. δH (d⁶ DMSO) 11.83 (1H, bs), 9.91 (1H,s), 8.73 (1H, s), 8.51 (1H, s), 8.50-8.47 (1H, m), 7.78-7.73 (2H, m),7.53 (1H, dt, J 7.2, 0.8 Hz) and 7.27-7.13 (4H, m).

EXAMPLE 665-Cyano-N-[4-2-imidazol-1-ylethoxy)phenyl]-4-indol-3-ylpyrimidine-2-amine

[0263] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (300 mg,1.25 mmol), 4-(2-imidazol-1-ylethoxy)phenylguanidinium nitrate (465 mg,1.25 mmol) and sodium hydroxide (100 mg, 2.5 mmol) to give the titlecompound (150 mg) as a yellow solid, m.p. 238-239°. δH (d⁶ DMSO) 12.02(1H, bs), 10.04 (1H, s), 8.72 (1H, s), 8.55 (1H, s), 8.33 (1H, bm), 7.68(1H, s), 7.63-7.55 (3H, m), 7.28-7.23 (2H, m), 7.22-7.05 (2H, bm),6.98-6.91 (3H, m), 4.52 (2H, t, J 5.0 Hz) and 4.26 (2H, t, J 5.0 Hz).

EXAMPLE 675-Cyano-4-pyridin-3-yl-N-{4-[2-(1,2,4-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-amine

[0264] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (800 mg,3.97 mmol), 4-[2-(1,2,4-triazol-1-yl)ethoxy]phenylguanidinium nitrate(1.23 g, 3.97 mmol) and sodium hydroxide (176 mg, 4.4 mmol) to give thetitle compound (1.0 g) as a yellow solid, m.p. 180-181°. δH (d⁶ DMSO)10.45 (1H, bs), 9.07 (1H, d, J 1.8 Hz), 8.93 (1H, s), 8.77 (1H, dd, J4.8, 1.5 Hz), 8.55 (1H, s), 8.29 (1H, d, J 8.1 Hz), 7.97 (1H, s),7.64-7.60 (3H, m), 6.91 (2H, d, J 9.0 Hz), 4.56 (2H, t, J 5.0 Hz) and4.32 (2H, t, J 5.0 Hz).

EXAMPLE 685-Cyano-4-pyridin-3-yl-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-amine

[0265] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (516 mg,2.56 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium nitrate(800 mg, 2.56 mmol) and sodium hydroxide (113 mg, 2.82 mmol) to give thetitle compound (531 mg) as a yellow solid, m.p. 177-178°. δH (d⁶ DMSO)10.45 (1H, bs), 9.08 (1H, s), 8.93 (1H, s), 8.78 (1H, dd, J 4.8, 1.5Hz), 8.31-8.28 (1H, m), 8.17 (1H, s), 7.73 (1H, s), 7.65-7.60 (3H, m),6.92 (2H, d, J 9.0 Hz), 4.77 (2H, t, J 5.0 Hz).

EXAMPLE 695-Cyano-4-pyridin-3-yl-N-{4-[2-(1,2,3-triazol-1-2-yl)ethoxy]phenyl}pyrimidine-2-amine

[0266] From 2-cyano-3-dimethylamino-1-pyridin-3-ylprope-1-one (800 mg,3.97 mmol), 4-[2-(1,2,3-triazol-2-yl)ethoxy]phenylguanidinium nitrate(1.23 g, 3.97 mmol) and sodium hydroxide (176 mg, 4.4 mmol) to give thetitle compound (970 mg) as a yellow solid, m.p. 179-180°. δH (dl DMSO)10.45 (1H, bs), 9.08 (1H, d, J 1.6 Hz), 8.93 (1H, s), 8.78 (1H, dd, J5.0, 1.6 Hz), 8.32-8.27 (1H, m), 7.79 (2H, s), 7.65-7.59 (3H, m), 6.90(2H, d, J 9.1 Hz), 4.78 (2H, t, J 5.2 Hz) and 4.46 (2H, t, J 5.1 Hz).

EXAMPLE 705cyano-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}-4-thien-3-ylpyrimidine-2-amine

[0267] From 2-cyano-3-dimethylamino-1-thien-3-ylpropen-1-one (557 mg,2.7 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium nitrate(920 mg, 3.0 mmol) and sodium hydroxide (1 30 mg, 3.2 mmol) to give thetitle compound (710 mg) as a yellow solid, m.p. 177°. δH (d⁶ DMSO) 10.28(1H, s), 8.84 (1H,s), 8.48 (1H, s), 8.18 (1H, d, J 0.8 Hz), 7.78-7.73(3H, m), 7.61 (2H, d, J 7.6 Hz), 6.91 (2H, d, J 8.9 Hz) and 4.77 (2H, t,J 5.0 Hz).

[0268] 2-Cyano-3dimethylamino-1-thien-3-ylpropen-1-one was prepared from3-cyanoacetyl thiophene (7.64 g,50.56 mmol) and dimethylformamidedimethylacetal (20 mL, 152 mmol) as a yellow solid (6.6 g), m.p. 134°.δH (CDCl₃) 8.27 (1H, dd, J 3.0, 1.3 Hz), 8.00 (1H, s), 7.61 (1H, dd, J5.0 Hz), 7.27 (1H, dd, J 5.0, 3.0 Hz), 3.48 (3H, s) and 3.29 (3H, s).

[0269] 3-Cyanoacetylthiophene was prepared in a similar manner to theanalogous starting material of Example 8 from 3-isoxazol-5-ylthiophene(8.15 g, 53.9 mmol) and a freshly prepared solution of sodium ethoxide[1.24 g, 53.9 mmol sodium in ethanol (100 mL)] to give the desiredmaterial (7.76 g) as an orange solid, δH (CDCl₃) 8.16 (1H, dd, J 5.0,1.3 Hz), 7.55 (1H, dd, J 5.0,2.3 Hz), 7.40 (1H, dd, J 5.0, 2.3 Hz) and3.96 (2H, m).

[0270] 3-Isoxazol-5-ylthiophene was prepared in a similar manner to theanalogous starting material of Example 8 from3-dimethylamino-1-thien-3-ylpropen-1-one (10 g, 55.2 mmol) andhydroxylamine hydrochloride (4.2 g, 60.7 mmol) to give the desiredproduct (8.15 g) as a colourless oil, δH (CDCl₃) 8.18 (1H, d, J 1.9 Hz),7.72 (1H, t, J 2.1 Hz), 7.34 (2H, d, J 2.1 Hz) and 6.29 (1H, d, J 1.8Hz).

[0271] 3-dimethylamino-1-thien-3-ylpropen-1-one was prepared from3-acetylthiophene (15.0 g) and dimethylformamide dimethylacetal (47.5mL, 357 mmol) as a yellow solid (14 g), m.p. 98°. δH (CDCl₃) 7.90 (1H,dd, J 3.0, 1.0 Hz), 7.76 (1H, d, J 12.4 Hz), 7.53 (1H, dd, J 5.9,1.0Hz), 7.28-7.25 (1H, m), 5.57 (1H,d, J 12.4 Hz) and 3.03 (6H, bs).

EXAMPLE 715-Cyano-N-[4-(2-(1,2,4-triazol-1-ylethyl)phenyl]-4-thien-3-ylpyrimidine-2-amine

[0272] From 2-cyano-3-dimethylamino-1-thien-3-ylpropen-1-one (800 mg,3.9 mmol), 4-[2-(1,2,4-triazol-1-yl)ethyl]phenylguanidinium nitrate(1.26 g, 4.3 mmol) and sodium hydroxide (186 mg, 4.7 mmol) to give thetitle compound (721 mg) as a light orange solid, m.p. 209°. δH (d⁶ DMSO)10.37 (1H, s), 8.88 (1H, s), 8.49 (1H, s), 8.31 (1H, s), 7.94 (1H, s),7.80-7.76 (2H, m), 7.63 (2H, d, J 8.5 Hz), 7.10 (2H, d, J 8.5 Hz), 4.41(2H, t, J 7.0 Hz) and 3.07 (2H, t, J 7.0 Hz).

[0273] 4-[2-(1,2,4-Triazol-1-yl)ethyl]phenylguanidinium nitrate wasprepared from 4-[2-(1,2,4-triazol-1-yl)ethyl]aniline (5.75 g, 30.4mmol), cyanamide (2.17 g, 51.7 mmol in water [2 mL]) and concentratedHNO₃ (2.2 mL, 33.3 mmol) as a pink solid, m.p. 183°. δH (d⁶ DMSO)9.40(1H, bs), 8.33 (1H, s), 7.94 (1H, s), 7.27-7.19 (4H,m), 7.14-7.11 (2H,m), 4.42 (2H, t,J 7.2 Hz) and 3.11 (2H, t, J 7.2 Hz).

[0274] 4-[2-(1,2,4-triazol-1-yl)ethyl]aniline was prepared from4-[2-(1,2,4-triazol-1-yl)ethyl]-nitro benzene (7.0 g, 32.1 mmol) in amanner similar to the analogous intermediate of Example 12 as an offwhite solid (5.8 g), m.p. 79°. δH 7.93 (1H, s), 7.73 (1H, s), 6.79 (2H,d, J 8.5 Hz), 6.58 (2H, d, J 8.5 Hz), 4.31 (2H, t, J 7.0 Hz), 3.30(2H,bs) and 3.03 (2H,t, J 7.0 Hz).

[0275] 4-[2-(1,2,4-triazol-1-yl)ethyl]nitrobenzene was prepared from4-[2-p-toluenesulphonyloxy ethyl]nitrobenzene (2.77 g, 8.6 mmol) and1,2,4-triazole sodium salt (942 mg, 10.3 mmol) as a pink solid (2.0 g),m.p. 97°. δH (CDCl₃) 8.12 (2H, d, J 9.0 Hz), 8.00 (1H, s), 7.80 (1H, s),7.20 (2H, m), 4.44 (2H, t, J 7.0 Hz) and 3.32 (2H, t, J 7.0 Hz).

[0276] 4-[2-p-toluenesulphonyloxyethyl]nitrobenzene was prepared from4-nitro-phenethyl alcohol (20.0 g, 120 mmol) and 4-toluenesulphonylchloride (34.2 g, 180 mmol) as a yellow solid (3.0 g), m.p. 133°. δH(CDCl₃) 8.10 (2H, d, J 9.0 Hz), 7.66 (2H, d, J 9.0 Hz), 7.26 (4H, m),4.29 (2H, t, J 6.0 Hz), 3.07 (2H, t, J 6.0 Hz) and 2.43 (3H, s).

EXAMPLE 724-(2-Aminopyridin-5-yl)-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine

[0277] To a suspension of5-cyano-N-(4-fluorophenyl)-4-[2-(4-methoxy-benzylamino)pyridin-5-yl]pyrimidine-2-amine(104 mg, 0.24 mmol) in acetonitrile (4 mL), MeOH (2 mL) anddichloromethane (2 mL), was added dropwise a solution of ceric ammoniumnitrate (133 mg, 0.24 mmol) in water (1 mL). After 0.5 h the reactionwas poured into saturated NaHCO₃ and extracted with CHCl₂. The organicphase was dried (MgSO₄) and concentrated under reduced pressure to givethe title compound (42 mg) as a buff solid, m.p. 289°. δH (d⁶ DMSO) 9.93(1H, s), 8.76 (1H, d, J 2.3 Hz), 8.74 (1H, s), 8.09 (1H, dd, J 8.8, 2.5Hz), 7.77-7.73 (2H, bm), 7.18-7.13 (2H, m), 6.85 (1H, s) and 6.63 (1H,d, J 8.8 Hz).

[0278]5-cyano-N-(4-fluorophenyl)-4-[2-(4-methoxybenzylamino)pyridin-5-yl]-pyrimidine-2-aminewas prepared in a similar manner to the title compound of Example 7 from4-(2-chloropyridin-5-yl)-5-cyano-N-(4-fluoro-phenyl)pyrimidine-2-amine(764 mg, 2.3 mmol) and p-methoxybenzyl-amine (644 mg, 4.6 mmol) as ayellow solid (432 mg). δH (d⁶ DMSO) 10.35 (1H, s), 8.82 (1H, s), 8.77(1H, d, J 2.3 Hz), 8.04 (1H, dd, J 8.9, 2.3 Hz), 7.84 (1H, t, J 5.6 Hz),7.77-7.74 (1H, m), 7.28 (2H, d, J 8.6 Hz), 7.21 (2H, t, J 8.9 Hz), 6.90(2H, d, J 8.6 Hz), 6.66 (1H, d, J 8.9 Hz), 4.51 (2H, s) and 3.73 (3H,s).

[0279]4-[2-Chloropyridin-5-yl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-aminewas prepared from 1-(2-chloropyridin-5-yl)2-cyano-3-dimethylaminopropen-1-one (8.0 g, 36 mmol), 4-fluorophenylguanidinium nitrate (8.23g, 37.8 mmol) and sodium hydroxide (1.49 g, 37.8 mmol) as a yellow solid(7.23 g). δH (d⁶DMSO) 10.66 (1H, bs), 9.00 (1H, s), 8.95 (1H, d, J 2.3Hz), 8.38 (1H, dd, J 8.4, 2.5 Hz), 7.80 (1H, d, J 8.4 Hz), 7.77-7.74(2H, m) and 7.24-7.20 (2H, m).

EXAMPLE 735-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl)pyrimidine-2-amine

[0280] From4-[2-Chloropyridin-5-yl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine(600 mg, 1.8 mmol) and N,N-diethylethylenediamine (430 mg) in a manneranalogous to the compound of Example 7, to give the title compound (197mg) as a yellow solid, m.p. 166°. δH (d⁶ DMSO) 9.79 (1H, bs), 8.83 (1H,d, J 2.3 Hz), 8.72 (1H, s), 8.08 (1H, dd, J 8.9, 2.3 Hz), 7.76-7.72 (2H,m), 7.17-7.11 (2H, m), 6.73 (1H, bs), 6.65 (1H, d, J 8.9 Hz), 3.53-3.48(2H, m), 2.85 (2H, bs), 2.73-2.69 (2H, m), 2.61-2.51 (4H, m) and1.78-1.70 (4H, m).

EXAMPLE 744-[4-(1-Acetamido-1-methylethyl)phenyl]-5-cyano-N-4-fluorophenylpyrimidine-2-amine

[0281] To a suspension of the compound of Example 20 (100 mg 0.29 mmol)in CHCl₃ (8 mL) was added pyridine (0.1 mL) and acetic anhydride (0.1mL). The reaction was stirred at ambient temperature for 6 h. Thereaction was then washed with 2M HCl and saturated NaHCO₃, dried(MgSO₄), and concentrated under reduced pressure to give the titlecompound (103 mg) as a yellow solid, m.p. 212-216°. δH 8.69 (1H. s),8.06 (2H, d, J 8.4 Hz), 7.63-7.60 (2H, m), 7.56 (2H, d, J 8.4 Hz),7.12-7.08 (2H, m), 5.82 (1H, s), 2.03 (3H, s) and 1.74 (6H, s).

EXAMPLE 755-Cyano-4-[4-(1-dimethylamino-1-methylethyl)phenyl]-N-(4-fluorophenyl])pyrimidine-2-amine

[0282] The compound of Example 20 (500 mg, 1.44 mmol) was heated atreflux in formic acid (10 mL) and 37% aqueous formaldehyde (10 mL) for4days. The reaction was diluted in 100 mL dichloromethane andconcentrated under reduced pressure. The resulting residue wasredissolved in dichloromethane (100 mL) and washed with 2M NaOH, dried(MgSO₄) and again concentrated under reduced pressure. The residue wassubjected to column chromatography (silica 10-15% MeOH-dichloromethane)to give the title compound (411 mg) as a yellow solid, m.p. 179°. δH(CDCl₃) 8.61 (1H, s), 7.94 (2H, d, J 8.1 Hz), 7.63 (2H, d, J 8.3 Hz),7.51-7.48 (2H, s), 7.04-7.01 (2H, m), 2.12 (6H, s) and 1.32 (6H, s).

EXAMPLE 765-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4-(1-dimethylamino-1-methylethyl)phenyl]pyrimidine-2-amine

[0283] In a manner analogous to the compound of Example 75, from thecompound of Example 11 (750 mg, 1,76 mmol) to give the title compound(687 mg) as a yellow solid, m.p.235-237°. δH (d⁶ DMSO) 10.68 (I H, bs),9.23 (1H, s), 8.99 (1H, J 1.9 Hz), 8.21 (1H, s), 7.99-7.96 (4H, m), 7.85(2H, dd, J 7.1, 1.9 Hz), 7.72 (2H, d, J 8.5 Hz), 2.13 (6H, s) and 1.35(6H, s).

EXAMPLE 775-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine

[0284] To a solution of the compound (1.0 g,2.88 mmol) of Example 20 inDMF (20 mL) was added potassium carbonate (786 mg, 5.7 mmol) and1,4-dibromobutane (622 mg, 2.88 mmol) and the resulting mixture stirredat 60° for 12 h. The reaction was partitioned between brine and ethylacetate then the organic phase was dried (MgSO₄) and concentrated underreduced pressure. The residue was subjected to column chromatography togive the title compound (591 mg) as a yellow solid, m.p. 124°. δH (d⁶DMSO) 8.58 (1H, s), 7.94 (2H, dapp, J 8.4 Hz), 7.63 (4H, m), 6.96 (2H,tapp, J 8.7 Hz), 3.23 (4H, s), 2.61 (4H, s) and 1.47 (6H, s).

EXAMPLE 785-Cyano-4-{[4-(imidazol-1-yl)methyl]phenyl}-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine

[0285] From2-cyano-3-dimethylamino-1-[(4-imidazol-1-ylmethyl)phenyl]propen-1-one(260 mg, 0.89 mmol), 3,4,5-trimethoxyphenylguanidinium nitrate (308 mg,1.07 mmol) and sodium hydroxide (46 mg, 1.16 mmol) in a similar mannerto the compound of Example 1 to give the title compound (80 mg) as ayellow solid, m.p. 253°. δH (d⁶ DMSO) 10.07 (1H, bs), 8.86 (1H, s), 7.99(2H, dt, J 8.4, 1.9 Hz), 7.72 (1H, s), 7.43 (2H, dt, J 8.4,1.9 Hz), 7.21(2H, s), 7.17 (1H, t, J 1.2 Hz), 6.94 (1H, t, J 2.1 Hz), 5.31 (2H, s),3.77 (6H, s) and 3.67 (3H, s).

[0286]2-Cyano-3-dimethylamino-1-[(4-imidazol-1-ylmethyl)phenyl]propen-1-onewas prepared by the addition of3-hydroxy-3-(4-(imidazol-1-ylmethyl)phenyl)acrylonitrile, lithium salt(2.16 g, 10.0 mmol) to a solution of MeOH-acetyl chloride (15 mL-1 mL)followed by dimethylformamide dimethylacetal (1.3 mL). The reaction wasstirred at room temperature for 1 h, then concentrated under reducedpressure. The resulting residue was partitioned between ethyl acetateand saturated Na₂CO₃. The organic phase was dried (MgSO₄) andconcentrated under reduced pressure. After chromatography (silica, 5-8%MeOH—CH₂Cl₂) of the residue the desired material was obtained as ayellow oil (260 mg). δH (300 MHz) 7.94 (1H, s), 7.75 (2H, dt, J 8.3, 1.8Hz), 7.54 (1H, s), 7.16 (2H, d, J 8.5 Hz), 7.08 (1H, t, J 1.0 Hz), 6.89(1H, t, J 1.3 Hz), 5.14 (2H, s), 3.46 (3H, s) and 3.28 (3H, s).

[0287] 3-Hydroxy-3-(4-(imidazol-1-ylmethyl)phenyl)acrylonitrile, lithiumsalt was prepared as follows:-Acetonitrile (1.04 mL, 20.0 mmol) wasadded to a solution of lithium bistrimethylamide (20 mL 1.0M in THF,20.0 mmol) at −78° under a nitrogen atmosphere, and the resultingmixture stirred for 20 min. A solution of methyl4-(imidazol-1-ylmethyl)benzoate (2.16 g, 10 mmol) in THF was addeddropwise and the reaction temperature then allowed to warm to roomtemperature over a 3 h period. The reaction was diluted with diethylether (30 mL) and the resulting solid collected by filtration washingfurther with ether (3×30 mL). The solid was dried under vacuum to givethe desired material as a yellow solid (2.65 g) and was used withoutpurification. δH (d⁶ DMSO) 7.72 (1H, s), 7.59 (2H, d, J 8.1 Hz), 7.15(1H, s), 7.10 (2H, d, J 8.2 Hz), 6.88 (1H, s), 5.13 (2H, s) and 3.93(1H, s).

EXAMPLE 795-Cyano-N-[3-fluorophenyl]-4-[4-(imidazol-1-yl)phenyl]pyrimidine-2-amine

[0288] From2-cyano-3-dimethylamino-1-(4-imidazol-1-ylphenyl)propen-1-one (480 mg,1.8 mmol), 3-fluorophenylguanidinium nitrate (480 mg, 1.98 mmol) andsodium hydroxide (87 mg) in a similar manner to the compound of Example1 to give the title compound (412 mg) as a yellow solid, m.p. 300°. δH(d ⁶ DMSO) 10.73 (1H, s), 9.03 (1H, s), 8.44 (1H, s), 8.12 (2H, d, J 9.0Hz), 7.96-7.90 (3H, m), 7.80 (1H, d, 1 Hz), 7.55 (1H, d, J 8.0 hz), 7.35(1H, q, J 9.0 Hz), 7.16 (1H, d, J 1.0 Hz) and 6.90 (1H, m).

[0289] 2-Cyano-3-dimethylamino-1-(4-imidazol-1-ylphenyl)propen-1-one wasprepared in a manner similar to the analogous starting material ofExample 79, as a yellow solid (970 mg), m.p. 165°. δH (CDCl ₃) 8.01 (1H,s), 7.96-7.92 (3H, m), 7.48-7.45 (2H, m), 7.33 (1H, t, J 1.4 Hz), 7.23(1H, d, J 1.0 Hz), 3.52 (3H, s) and 3.34 (3H, s).

[0290] 3-Hydroxy-3-(4-imidazol-1-ylphenyl)acrylonitrile, sodium salt wasprepared from 5-(4-imidazol-1-ylphenyl)isoxazole (1.22 g, 5.78 mmol) andsodium (133 mg, 5.78 mmol) in ethanol (15 mL) in a manner silimilar tothe analogous starting material of Example 8, as a beige solid (1.14 g),m.p. 286°.

[0291] 5-(4-Imidazol-1-ylphenyl)isoxazole was prepared by treating asolution of 3-dimethylamino-1-[(4-imidazol-1-yl)phenyl]propen-1-one(1.64 g, 6.8 mmol) in MeOH with hydroxylamine-O-sulphonic acid (831 mg,7.35 mmol) at ambient temperature for 16 h. A further quantity ofhydroxylamine-O-sulphonic acid (831 mg, 7.35 mmol) was added andstirring continued for 3 h. The reaction was then treated with saturatedNaHCO₃ solution, the resulting solution being collected by filtrationand washed with water and diethyl ether to give the desired material(1.08 g) as a pink solid, m.p. 168°. ______δH (d⁶ DMSO) 8.67 (1H, d, J1.8 Hz), 3.89 (1H, s), 8.03-7.99 (2H, m), 7.86-7.84 (3H, m), 7.14 (1H,s) and 7.10 (1H, d, J 1.9 Hz).

EXAMPLE 80N-[3-(5Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide

[0292] A solution ofN-3-aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amine (300 mg, 1.0mmol) and 4-(4-methylpiperazin-1-yl)methylbenzoic acid, lithium salt(300 mg, 1.0 mmol) in DMF (10 mL) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (307 mg, 1.6 mmol),1-hydroxybenzotriazole (216 mg, 1.6 mmol) and N-methylmorpholine (350ml, 3.2 μmol) and the resulting mixture was stirred at ambienttemperature for48 h. The reaction was then concentrated under reducedpressure and the resulting residue partitioned between ethyl acetate andsaturated brine. The organic phase was dried (MgSO4), concentrated underreduced pressure and the resulting residue recrystallised from ethylacetate-ether-MeOH (4:4:1) to give the title compound (312 mg) as acolourless solid, m.p. 208-209°. δH (d ⁶ DMSO) 10.48 (1H, bs), 10.23(1H, s),8.89 (1h,s), 8.28 (1H, d, J 3.5 Hz), 8.13 (1H, m), 7.98 (1H, d,J 4.8 Hz), 7.90 (2H, d, J 8.2 Hz), 7.60 (1H, bs), 7.43 (3H, d, J 8.2Hz), 7.36-7.30 (2H, s), 3.52 (2H, s), 2.37 (8H, bs) and 2.15 (3H,s).

[0293] N-3-Aminophenyl-5-cyano4-thien-2-ylpyrimidine-2-amine wasprepared by heating a solution of5-cyano-N-3-nitrophenyl4-thien-2-ylpyrimidine-2-amine (2.77 g, 8.57mmol) and tin(II)chloride d1Hydrate (7.73 g, 34.05 mmol) in ethanol (160mL) at reflux for 18 h. On cooling the reaction was concentrated underreduced pressure and partitioned between CH₂Cl₂ and 2M NaOH. The organicphase was dried (MgSO₄) and evaporated to give the desired material (320mg) as a yellow solid, m.p. 221-222°. δH (d⁶ DMSO) 10.16 (1H, s), 8.83(1H, s), 8.24 (1H, d, J 3.9 Hz), 7.97 (1H, d, J 5.1 Hz), 7.32 (1H, dd, J5.0, 4.0 Hz), 6.97 (3H, bm), 6.31 (1H, m) and 5.04 (2H, bs).

[0294] 5-Cyano-N-3-nitrophenyl4-thien-2-ylpyrimidine-2-amine wasprepared from 2-cyano-3-dimethylamino-1-thien-2-ylpropen-1-one (3.20 g,15.51 mmol), 3-nitrophenylguanidinium nitrate (3.74 g, 15.53 mmol) andsodium hydroxide (652 mg, 7.82 mmol) to give the desired material (841mg) as an off-white solid, m.p.275-277°. δH (d⁶ DMSO) 10.87 (1H, bs),8.98 (1H, s), 8.90 (1H, bs), 8.31-8.29 (1H, m), 8.09-8.05 (2H, m), 7.91(1H, dd, J 7.7, 2.0 Hz), 7.64 (1H, t,J 8.1 Hz) and 7.37-7.35 (1H, m).

[0295] 4-(4-Methylpiperazin-1-yl)methylbenzoic acid, lithium salt wasprepared by stirring methyl 4-(4-methylpiperazin-1-yl)methylbenzoate(845 mg, 3.41 mmol) and lithium hydroxide monohydrate (300 mg, 7.15mmol) in THF-H20[50% v/v] (14 mL) at room temperature for 16 h. Thesolvent was removed under reduced pressure to give the desired material(799 mg) as a white solid, m.p. 230°. δH (d⁶ DMSO) 7.80 (2H, d, J 8.1Hz), 7.16 (2H,d, J 8.1 Hz), 3.41 (2H, s), 2.30 (8H, bs) and 2.12 (3H,s).

[0296] Methyl 4-(4-methylpiperazin-1-yl)methylbenzoate was prepared byheating methyl (4-bromomethyl)benzoate (2.3 g, 10.0 mmol) and1-methylpiperazine (1.0 g, 10.0 mmol) in DMF (10 mL) for 3 h. Thereaction was concentrated under reduced pressure and the residue driedunder high vacuum to give the desired product (1.2 g) as a white solid,m.p.152°. δH (d⁶ DMSO) 7.90 (2H, d, J 8.2 Hz), 7.43 (2H, d, J 8.2 Hz),3.83 (3H, s), 2.67 (4H, bs), 2.47 (4H, bs) and 2.40 (3H, s).

EXAMPLES 81 to 104

[0297] The compounds of Examples 81 to 104 were prepared by solutionphase parallel synthesis performed on a Quest 210 Personal Synthesizer(Argonaut Technologies, San Carlos, Calif., USA) employing the followingintermediate:

2-Chloro-5-cyano-4-phenylpyrimidine

[0298] 5-cyano-4-phenyl-1(H)-pyrimidin-2-one (0.83 g, 4.21 mmol) washeated in phosphorous oxychloride (20 mL) and DMF (˜1 ml) at 115° for 24h. On cooling, the reaction was concentrated under reduced pressure andthe residue poured into a cooled saturated NaHCO₃ solution. This wasextracted with ethyl acetate, the combined organic phases dried (MgSO₄)and evaporated to give the desired material (0.79 g) as a yellow solidm.p. 79-81°.

[0299] The pyrimidin-2-one was prepared by treating a solution of2-amino-5-cyano-4-phenylpyrimidine (2.0 g, 10.2 mmol) in 50%concentrated H₂SO₄-water (v/v) at room temperature, with a solution ofsodium nitrite (2.82 g, 40.8 mmol) in water (30 ml) over 1 h. Thereaction was allowed to stir overnight at room temperature, beforeadditional sodium nitrite (2.82 g, 10.2 mmol) was added and stirringcontinued for 3 h. After this time ammonium hydroxide (33% aqueous) wasadded to pH9, and the resulting precipitate collected and dried to givethe desired material (2.2 g) as a white solid m.p. 220-222°.

[0300] 2-Amino-5-cyano-4-phenylpyrimidine was prepared from guanidinecarbonate (1.57 g, 17.5 mmol),1-phenyl-2-cyano-3-dimethylaminopropen-1-one (3.5 g, 17.5 mmol) andsodium hydroxide (720 mg, 19.3 mmol) in a similar method to the compoundof Example 1, as an off-white solid, m.p. 147°.

EXAMPLE 81 5-Cyano-4-phenyl-N-guinol-6-ylpyrimidine-2-amine

[0301] To a Quest 5 ml Teflon reaction vessel (RV), was added6-aminoquinoline (61 μmol) and a solution of2-chloro-5-cyano-4-phenylpyrimidine (10 mg, 47 mmol) in 1,4-dioxan (1.5mL). The resulting mixture was heated (85°) with agitation every 10 minfor 48 h. After this time PS-isocyanate resin (Argonaut Technologies)(100 mg, 150 μmol) and PS-trisamine (Argonaut Technologies) (50 mg, 150mmol) were added to the reaction vessel and the reaction was agitatedevery 10 min at 55° for 18 h. The reaction was diluted with THF (˜3 ml)and then filtered into a pre-weighed vial, the resins being furtherwashed with dichloromethane. The combined filtrates were evaporatedunder reduced pressure overnight and the residue taken up in DMSO (500μl). The residue was purified using semi-preparitive HPLC (System;Waters HPLC Pump Module 600E, Waters 486 detector with semi-prep flowcell and Waters 717 Autosampler (250 μl). Column; 150×10 mm Luna C18 (2)5 μm. Conditions; 90% [0.1% TFA-water] 10% [0.1% TFA-acetonitrile] to10% [0.1% TFA-water] 90% [0.1% TFA-acetonitrile] at 5.0 mlmin⁻¹ with arun time of 15 min at ambient temperature) to give the title compound.HPLC-MS Retention time 4.2 mins (MH)+ 324.

[0302] HPLC-MS Conditions

[0303] HPLC-MS was performed on a Hewlett Packard Binary Pump 1100/MSDES Single Quadropole using a Luna C18(2), 50×4.6 mm column, running agradient of 95% [20 mM ammonium formate pH3.5] 5% [acetonitrile-0.1%TFA] to 5% [20 mM ammonium formate pH3.5] 95% [acetonitrile-0.1% TFA] at0.8 mlmin⁻¹ with a run time of 5 min. MS acquired at 70V in positive ionAPI-electrospray mode of ionisation, scannining from 150-750 amu.

EXAMPLE 82N-(3-Chloro-4-methylphenyl)-5-cyano-4-phenylpyrimidine-2-amine

[0304] 3-Chloro4-methylaniline gave the title compound

[0305] HPLC-MS Retention time 5.13 mins (MH)+ 322

EXAMPLE 83 N-(3-Acetylphenyl)-5-cyano-4-phenyloyrimidine-2-amine

[0306] 3-Aminoacetophenone gave the title compound

[0307] HPLC-MS Retention time 4.42 mins (MH)+ 315

EXAMPLE 84N-(4-Chloro-3-trifluoromethylphenyl)-5-cyano-4-phenylpyrimidine-2-amine

[0308] 4-Chloro-3-trifluoromethylaniline gave the title compound

[0309] HPLC-MS Retention time 5.19 mins (MH)+ 376

EXAMPLE 855-Cyano-N-(4-methoxycarbonylphenyl)-4-phenylpyrimidine-2-amine

[0310] Methyl 4-aminobenzoate gave the title compound

[0311] HPLC-MS Retention time 4.58 mins (MH)+ 331

EXAMPLE 86 N-(4-Carboxymethylphenyl)-5-cyano-4-phenylpyrimidine-2-amine

[0312] 4-Aminophenylacetic acid gave the title compound

[0313] HPLC-MS Retention time 4.0 mins (MH)+ 331

EXAMPLE 875-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenyloyrimidine-2-amine

[0314] Procainamide hydrochloride gave the title compound

[0315] HPLC-MS Retention time 3.33 mins (MH)+ 415.5

EXAMPLE 88 N-(3-Carboxyphenyl)-5-cyano-4-phenylpyrimidine-2-amine

[0316] 3-Aminobenzoic acid gave the title compound

[0317] HPLC-MS Retention time 4.03 mins (MH)+ 317

EXAMPLE 895-Cyano-4-phenyl]-N-[3-(1,1,2,2-tetrafluoroethoxyphenyl)lpyrimidine-2-amine

[0318] 1,1,2,2-Tetrafluoroethoxyaniline gave the title compound

[0319] HPLC-MS Retention time 4.77 mins (MH)+ 389

EXAMPLE 90 5-Cyano-N-(3-oxazol-5-ylphenyl)-4-phenyl]pyrimidine-2-amine

[0320] 3-oxazol-5-ylaniline gave the title compound

[0321] HPLC-MS Retention time 4.4 mins (MH)+ 340

EXAMPLE 915-Cvano-N-[2-(4-fluorophenoxy)pyridin-5-yl)-4-phenylpyrimidine-2-amino

[0322] 5-Amino-2-(4-fluorophenoxy)pyridine gave the title compound

[0323] HPLC-MS Retention time 4.72 mins (MH)+ 384

EXAMPLE 925-cyano-N-(4-methoxycarbonylthien-3-yl)-4-phenylpyrimidine-2-amine

[0324] Methyl 3-aminothiophene4-carboxylate gave the title compound

[0325] HPLC-MS Retention time 5.09 min (MH)+ 337

EXAMPLE 935-Cyano-N-(2-morpholinopyridin-5-yl)-4-phenylpyrimidine-2-amine

[0326] 2-Morphilino-5-aminopyridine gave the title compound

[0327] HPLC-MS Retention time 4.1 min (MH)+ 359

EXAMPLE 945-Cyano-N-[4-(6-methylbenzothiazol-2-yl)phenyl]]pyrimidine-2-amine

[0328] 2-Amino-6-methylbenzothiazole gave the title compound

[0329] HPLC-MS Retention time 5.7 min (MH)+ 420.5

EXAMPLE 955-Cyano-N-(4-isopropyl-2-methylphenyl)-4-phenylpyrimidine-2-amine

[0330] 4-isopropyl-2-methylaniline gave the title compound

[0331] HPLC-MS Retention time 5.35 mins (MH)+ 329

EXAMPLE 965-Cyano-N-(3-methanesulphonyl)phenyl-4-phenylpyrimidine-2-amine

[0332] 3-(Methanesulphonyl)aniline gave the title compound

[0333] HPLC-MS Retention time 4.12 mins (MH)+ 351

EXAMPLE 975-Cyano-N-[2-(3,5-dimethylpyrazol-1-yl)pyridin-3-yl)-4-phenylpyrimidine-2-amine

[0334] 3-Amino-2-(3,5-dimethylpyrazol-1-yl)pyridine gave the titlecompound

[0335] HPLC-MS Retention time 5.12 mins (MH)+ 368

EXAMPLE 98 5-Cyano-N-(4-ethylphenyl)-4-phenylpyrimidine-2-amine

[0336] 4-Ethylaniline gave title compound

[0337] HPLC-MS Retention time 4.99 mins (MH)+ 301

EXAMPLE 99 5-Cyano-N-(8-methoxyguinol-6-yl)-4-phenylpyrimidine-2-amine

[0338] 6-Amino-8-methoxyquinoline sgave the title compound

[0339] HPLC-MS Retention time 3.96 mins (MH)+ 354

EXAMPLE 100 N-(4-n-Butoxyphenyl)-5-cyano-4-phenylpyrimidine-2-amine

[0340] 4-n-Butoxyaniline gave the title compound

[0341] HPLC-MS Retention time 5.19 mins (MH)+ 345.4

EXAMPLE 101 5-Cyano-N-(2-oxo-2-phenylethyl)-4-phenylgyrimidine-2-amine

[0342] 2-Oxo-2-phenethylamine gave the title compound

[0343] HPLC-MS Retention time 4.4 mins (MH)+ 315

EXAMPLE 1025-Cyano-N-[3-n-(4-methylpiperazin-1-yl)propyl]-4-phenylpyrimidine-2-amine

[0344] 3-N-(4-Methylpiperazin-1-yl)propylamine gave the title compound

[0345] HPLC-MS Retention time 3.1 mins (MH)+ 337

EXAMPLE 103 N-(Adamant-1-yl)-5-cyano-4-phenylpyrimidine-2-amine

[0346] 1-Adamantanamine gave the title compound

[0347] HPLC-MS Retention time 6.0 mins (MH)+ 331

EXAMPLE 104 5-Cyano-N-(2-morpholinoethyl)-4-phenylpyrimidine-2-amine

[0348] 2-Morpholinoethylamine gave the title compound

[0349] HPLC-MS Retention time 3.1 mins (MH)+ 310

EXAMPLE 105

[0350]4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-aminecitrate

[0351] The compound of Example 11 (100 mg, 0.25 mmol) was dissolved inacetone/methanol (25 mL, 1:1 v/v) and to this citric acid (52.5 mg, 0.25mmol) was added. The resulting solution was diluted with diethyl ether(20 ml) to give the title compound (145 mg). 6H (d⁰ DMSO) 10.73 (1H,bs), 9.21 (1H, s), 9.01 (1H, s), 8.20 (1H, s), 8.02 (2H, d, J 8.4 Hz),7.94 (2H, d, J 8.7 Hz), 7.80 (2H, d, J 7.4 Hz, 7.78 (2H, d, J 8.3 Hz),2.49 (4H, m) and 1.65 (6H, s)

Biological Activity

[0352] The following assays were used to demonstrate the activity andselectivity of compounds according to the invention:

[0353] The activity of the comounds against KDR kinase and a FGFR Kinase[FGFR2 kinase] can be determined in the following two assays:

[0354] KDR Kinase and FGFr2 Kinase

[0355] The activities of recombinant KDR kinase and FGFr2 kinase weredetermined by measuring their ability to transfer the γ-phosphate from[³³P]ATP to polyglutamic acid—tyrosine (pEY).

[0356] The assay methodology employed for both kinases is identicalexcept that in the assay of KDR kinase the diluent used throughout was20 mM HEPES pH 7.25 containing 2 mM MnCl₂, 2mM MnCl₂, 5mM DTT and 0.05%Brij 35, whereas in the FGFr2 assay 10 mM MnCl₂ is used instead of 2 mMMnCl₂ and 2 mM MnCl₂.

[0357] The assay was conducted in a total volume of 202 μl containing1-10 ng kinase, 5 μg/ml pEY (4:1) (Sigma, UK), 1 μM ATP (containing˜50,000 cpm [³³P]ATP (Amersham International, UK) (Sigma, UK) and testinhibitors at the appropriate concentration. The test inhibitors weredissolved in DMSO and added such that the final concentration of DMSO inthe assay did not exceed 2% (v/v). The assay was initiated by additionof kinase and terminated after 10 minutes incubation at room temperatureby addition of 50 μl of 20 mM HEPES pH 7.25 containing 0.125M EDTA and10 mM ATP. A 200 μl aliquot was applied to the well of a Millipore (UK)MAFC filter plate containing 100 μl of 30% (w/v) trichloroacetic acid(TCA). The plate was then placed on a suitable manifold and connected toa vacuum. After complete elimination of the liquid each well was washedunder vacuum using five volumes (100 μl per wash) of 10% (w/v) TCA andfinally two volumes (100 μl per wash) of ethanol. The bottom of thefilter plate was then sealed and 100 μl per well of Ultima Gold(Beckham, UK) scintillant was added to each well. The readioactivity wasmeasured using an appropiate scintillation counter such as a WallacTrilux or Packard TopCount. The IC₅₀ value for each inhibitor wasobtained from log dose inhibition curves fitted to the four-parameterslogistic equation.

[0358] In this assay compounds accoding to the invention have IC₅₀values of around 1 μM and below, the most active compounds having valuesof 100 nM and below.

[0359] The selectivity of compounds according to the invention can bedetermined in the following assays:

[0360] p56^(Ick) Kinase Assay

[0361] The tyrosine kinase activity of p56^(Ick) was determined using aRR-src peptide (RRLIEDNEYTARG) and [γ-³³P]ATP as substrates.Quantitation of the ³³P-phosphorylated peptide formed by the action ofp56^(Ick) was achieved using an adaption of the method of Geissler et al(J. Biol. Chem. (1990) 265, 22255-22261).

[0362] All assays were performed in 20 mM HEPES pH 7.5 containing 10 mMMgCl₂, 10 mM MnCl₂, 0.05% Brij, 1 μM ATP (0.5 μCi[γ-³³P]ATP) and 0.8mg/ml RR-src. Inhibitors in dimethylsulphoxide (DMSO) were added suchthat the final concentration of DMSO did not exceed 1%, and enzyme suchthat the consumption of ATP was less than 10%. After incubation at 30°C. for 15 min, the reaction was terminated by the addition of one-thirdvolume of stop reagent (0.25 mM EDTA and 33 mM ATP in dH₂O). A 15 μlaliquot was removed, spotted onto a P-30 filtermat (Wallac, MiltonKeynes, UK), and washed sequentially with 1% acetic acid and de-ionisedwater to remove ATP. The bound ³³P-RR-src was quantitated byscintillation counting of the filtermat in a Betaplate scintillationcounter (Wallac, Milton Keynes, UK) after addition of Meltilexscintillant (Wallac, Milton Keynes, UK).

[0363] The dpm obtained, being directly proportional to the amount of³³P-RR-src produced by p56^(Ick), were used to determine the IC₅₀ foreach compound. The IC₅₀ was defined as the concentration of compoundrequired to reduce the production of ³³P-RR-src by 50%.

[0364] In this test, compounds according to the invention have IC₅₀values of 10 μM and above.

[0365] Zap-70 Kinase Assay

[0366] The tyrosine kinase activity of Zap-70 was determined using acapture assay based on that employed above for p56^(Ick). The RR-srcpeptide was replaced with polyGlu-Tyr (Sigma; Poole, UK) at a finalconcentration of 17 μg/ml. After addition of the stopped reaction to thefiltermat, trichloroacetic acid 10% (w/v) was employed as the washreagent instead of acetic acid and a final wash in absolute ethanol wasalso performed before scintillation counting. IC₅₀ values weredetermined as described above in the p₅₆ ^(Ick) assay.

[0367] In this test the compounds of the invention have IC₅₀ values ofaround 10 μM and above.

[0368] EGFr Kinase Assay

[0369] The tyrosine kinase activity of the EGF receptor (EGFr) wasdetermined using a similar methodology to the p56^(Ick) kinase assay,except that the RR-src peptide was replaced by a peptide substrate forEGFr obtained from Amersham International pic (Little Chalfont, UK) andused at the manufacturer's recommended concentration. IC₅₀ values weredetermined as described previously in the p56^(Ick) assay.

[0370] Protein kinase C Assay

[0371] Inhibitor activity against protein kinase C (PKC) was determinedusing PKC obtained from Sigma Chemical Company (Poole, UK) and acommercially available assay system (Amersham International plc,Amersham, UK). Briefly, PKC catalyses the transfer of the γ-phosphate(³²p) of ATP to the threonine group on a peptide specific for PKC.Phosphorylated peptide is bound to phosphocellulose paper andsubsequently quantified by scintillation counting. The inhibitor potencyis expressed as either (i) the concentration required to inhibit 50% ofthe enzyme activity (IC₅₀) or (ii) the percentage inhibition achieved by10 μM inhibitor.

[0372] In this test the compounds of the invention have IC₅₀ values ofaround 10 μM and above.

1. A compound of formula (1):

wherein Ar is an optionally substituted aromatic or heteroaromaticgroup; R¹ is a hydrogen atom or a straight or branched chain alkylgroup; R² is a —X¹—R³ group where X¹ is a direct bond or a linker atomor group, and R³ is an optionally substituted aliphatic, cycloaliphatic,heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;and the salts, solvates, hydrates and n-oxides thereof.
 2. A compoundaccording to claim 1 wherein R¹ is a hydrogen atom.
 3. A compoundaccording to claim 1 wherein R² is a group —X¹R³ in which X¹ is a directbond.
 4. A compound according to claim 3 in which R³ is an optionallysubstituted aromatic or heteroaromatic group, said heteroaromatic groupcontaining one or two ring oxygen, sulphur and/or nitrogen atoms.
 5. Acompound according to claim 4 wherein R³ is a phenyl, thienyl,thiazolyl, indolyl or pyridyl group optionally substituted by one, twoor three —R^(4b) or -Alk(R^(4b))_(m) substituents in which R^(4b) is ahalogen atom, or an amino (—NH₂), substituted amino, nitro, cyano,hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO₂H),esterified carboxyl, thiol (—SH), substituted thiol, —COR⁵ [where R⁵is a-Alk(R⁴)_(m) aryl or heteroaryl group], —CSR⁵, —SO₃H, —SO₂R⁵, —SO₂NH₂,—SO₂NHR⁵, —SO₂N[R⁵]₂, —CONH₂, —CSNH₂, —CONHR⁵, —CSNHR⁵, —CON[R⁵]₂,—CSN[R⁵]₂, —NHSO₂H, —NHSO₂R⁵, —N[SO₂R⁵]₂, —NHSO₂NH₂, —NHSO₂NHR⁵,—NHSO₂N[R⁵]₂, —NHCOR⁵, —NHCONH₂, —NHCONHR⁵, —NHCON[R⁵]₂, —NHCSR⁵,—NHC(O)OR⁵, or optionally substituted cycloaliphatic,hetero-cycloaliphatic, aryl or heteroaryl group; Alk is a straight orbranched C₁₋₆ alkylene, C₂₋₆ alkenylene or C₂₋₆ alkynylene chain,optionally interrupted by one, two or three —O— or —S— atoms or groupsselected from —S(O)—, —S(O)₂— or —N(R⁶)— [where R⁶ is a hydrogen atom ora straight or branched chain C₁₋₆ alkyl group]; and m is zero or aninteger 1, 2 or
 3. 6. A compound according to claim 1 wherein Ar is aphenyl, pyridyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl,quinolyl, isoquinolyl or benzoxazolyl group each substituted by one, twoor three —R⁴ or -Alk(R⁴)_(m) substituents in which R⁴ is a halogen atom,or an amino (—NH₂), substituted amino, nitro, cyano, hydroxyl (—OH),substituted hydroxyl, formyl, carboxyl (—CO₂H), esterified carboxyl,thiol (—SH), substituted thiol, —COR⁵ [where R⁵ is a -Alk(R⁴)_(m), arylor heteroaryl group], —CSR⁵ —SO₃H, —SO₂R⁵, —SO₂NH₂, —SO₂NHR⁵, SO₂N[R⁵]₂,—CONH₂, —CSNH₂, —CONHR⁵, —CSNHR⁵, —CON[R⁵]₂, —CSN[R⁵]₂, —NHSO₂H,—NHSO₂R⁵, —N[SO₂R⁵]₂, —NHSO₂NH₂, —NHSO₂NHR⁵, —NHSO₂N[R⁵]₂, —NHCOR⁵,—NHCONH₂, —NHCONH R⁵, —NHCON[R⁵]₂, —NHCSR⁵, —NHC(O)OR⁵, or optionallysubstituted cycloaliphatic, hetero-cycloaliphatic, aryl or heteroarylgroup; Alk is a straight or branched C₁₋₆ alkylene, C₂₋₆ alkenylene orC₂₋₆ alkynylene chain, optionally interrupted by one, two or three —O—or —S— atoms or groups selected from —S(O)—, —S(O)₂— or —N(R⁶)— [whereR⁶ is a hydrogen atom or a straight or branched chain C₁₋₆ alkyl group];and m is zero or an integer 1, 2 or
 3. 7. A compound according to claim6 wherein Ar is a phenyl group substituted by one, two or three —R⁴ or-Alk(R⁴)_(m) substituents.
 8. A compound according to any one of claim 5to claim 7 wherein at least one of —R⁴, -Alk(R⁴)_(m), —R^(4b) or-Alk(R^(4b))_(m) is a —X^(1a)(Alk^(a))_(p)NR^(7a)R^(7b)) (where X^(1a)is a direct bond or a linker atom or group, Alk^(a) is as defined forAlk, p is zero or an integer 1 and R^(7a) and R^(7b) which may be thesame or different is each a hydrogen atom or a straight or branchedC₁₋₆alkyl group), —X^(1a)(Alk^(a))_(p)NHet¹ (where —NHet¹ is anoptionally substituted C₃₋₇cyclicamino group optionally containing oneor more —O— or —S— atoms or —N(R⁶) [where R⁶ is a hydrogen atom or astraight or branched chain C₁₋₆alkyl group]) or —X^(1a)(Alk^(a))_(p)Ar²group (where Ar² is a nitrogen containing heteroaromatic group).
 9. Acompound which is:5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonyl-phenyl)pyrimidine-2-amine;5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amine;5-Cyano-4-[2-(3(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol-5-yl)pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amine;5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylpyrimidine-2-amine;5-Cyano-(4phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4(1,2,3-triazol-1-yl)phenyl]pyrimidine-2-amine;4-[4(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine;N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide;4-[3(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-methyl-imidazol-1-yl)ethyl]phenyl}pyrimidine-2-amino;5-Cyano4-[4-(imiadzol-1-yl)methyl]phenyl-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amino;and the salts, solvates, hydrates and N-oxides thereof.
 10. A compoundwhich is:4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine;5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]4-[4-(1-dimethylamino-1-methylethyl)phenyl]pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]phenyl}pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine;5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl)pyrimidine-2-amine;4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrimidine-2-amine;and the salts, solvates, hydrates and N-oxides thereof.
 11. Apharmaceutical composition comprising a compound according to claim 1together with one or more pharmaceutically acceptable carriers,excipients or diluents